Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp)

ABSTRACT

A compound having the structure set forth in Formula (I) and Formula (II): 
     
       
         
         
             
             
         
       
     
     wherein the substituents Y, Z, A, B, R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.16/714,474, filed Dec. 13, 2019, now allowed, which is a continuation ofU.S. application Ser. No. 15/719,534, filed Sep. 28, 2017, now U.S. Pat.No. 10,534,209, which is a continuation of U.S. application Ser. No.14/632,825, filed Feb. 26, 2015, now U.S. Pat. No. 9,820,985, which is adivisional of U.S. patent application Ser. No. 13/787,496, filed Mar. 6,2013, now U.S. Pat. No. 8,999,987, which is a continuation of U.S.patent application Ser. No. 13/077,785, filed Mar. 31, 2011, now U.S.Pat. No. 8,420,650, which is a continuation of U.S. patent applicationSer. No. 12/510,096, filed Jul. 27, 2009, now U.S. Pat. No. 8,012,976,which claims the benefit of U.S. provisional applications Nos.61/173,088, filed Apr. 27, 2009, 61/151,036, filed Feb. 9, 2009, and61/086,687, filed Aug. 6, 2008, all of which are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with the enzyme poly(ADP-ribose)polymerase (PARP).

BACKGROUND OF THE INVENTION

The family of poly(ADP-ribose)polymerases (PARP) includes approximately18 proteins, which all display a certain level of homology in theircatalytic domain but differ in their cellular functions (Ame et al.,BioEssays, 26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique membersof the family, in that their catalytic activities are stimulated by theoccurrence of DNA strand breaks.

PARP has been implicated in the signaling of DNA damage through itsability to recognize and rapidly bind to DNA single or double strandbreaks (D'Amours, et al., Biochem. J., 342, 249-268 (1999)). Itparticipates in a variety of DNA-related functions including geneamplification, cell division, differentiation, apoptosis, DNA baseexcision repair as well as effects on telomere length and chromosomestability (d'Adda di Fagagna, et al., Nature Gen., 23(1), 76-80 (1999)).

SUMMARY OF THE INVENTION

Provided herein are compounds, compositions and methods for modulatingthe activity of PARP. Among the compounds that are provided herein, arecompounds that are inhibitors of PARP. Also described herein is the useof such compounds, compositions and methods for the treatment ofdiseases, disorders or conditions associated with the activity of PARP.

In some embodiments, compounds provided herein have the structure ofFormula (I) and Formula (II) and pharmaceutically acceptable salts,solvates, esters, acids and prodrugs thereof. In certain embodiments,provided herein are compounds having the structure of Formula (I) andFormula (II) that are inhibitors of the enzymepoly(ADP-ribose)polymerase (PARP).

Described herein are8-B,Z-2-R₄-4-R₁-5-R₂-6R₃-7R₅-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-ones, 8-B,Z-5-R₂-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-ones, in which A, B, Z, Y, R₁, R₂, R₃, R₄ and R₅ are further describedherein. In certain embodiments, isomers including enantiomers anddiastereoisomers, and chemically protected forms of compounds having astructure represented by Formula (I) and Formula (II) are also provided.

Formula (I) is as follows:

wherein:Y and Z are each independently selected from the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3 R₆;        wherein each R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3 R₆;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene;        R₁, R₂, and R₃ are each independently selected from the group        consisting of hydrogen, halogen, alkenyl, alkoxy,        alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy,        haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR_(A)R_(B),        NR_(A)R_(B)alkylene, and (NR_(A)R_(B))carbonyl;        A and B are each independently selected from hydrogen, Br, Cl,        F, I, OH, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl        wherein C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are        optionally substituted with at least one substituent selected        from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, and C₃-C₅cycloalkyl,        wherein B is not OH;        R_(A), and R_(B) are independently selected from the group        consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or        R_(A) and R_(B) taken together with the atom to which they are        attached form a 3-10 membered heterocycle ring optionally having        one to three heteroatoms or hetero functionalities selected from        the group consisting of —O—, —NH, —N(C₁-C₆-alkyl)-,        —NCO(C₁-C₆-alkyl)-, —N(aryl)-, —N(aryl-C₁-C₆-alkyl-)-,        —N(substituted-aryl-C₁-C₆-alkyl-)-, —N(heteroaryl)-,        —N(heteroaryl-C₁-C₆-alkyl-)-,        —N(substituted-heteroaryl-C₁-C₆-alkyl-)-, and —S— or S(O)_(q)—,        wherein q is 1 or 2 and the 3-10 membered heterocycle ring is        optionally substituted with one or more substituents;        R₄ and R₅ are each independently selected from the group        consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl,        haloalkyl, hydroxyalkylene, and (NR_(A)R_(B))alkylene;        and isomers, salts, solvates, chemically protected forms, and        prodrugs thereof.

Formula (II) is as follows:

wherein:Y is an aryl or heteroaryl group optionally substituted with at leastone R₆;Z is an aryl group optionally substituted with at least one R₆;A and B are each independently selected from hydrogen, Br, Cl, F, I, OH,C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH;R₆ is selected from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl; C₂-C₆alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl,arylalkyl, C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio,heteroarylalkylthio, heterocycloalkoxy, C₂-C₈heterocycloalkylthio,heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene;R₂ is selected from hydrogen, Br, Cl, I, or F;R_(A), and R_(B) are independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₃-C₈cycloalkyl, and alkylcarbonyl; or R_(A) andR_(B) taken together with the atom to which they are attached form a3-10 membered heterocycle ring optionally having one to threeheteroatoms or hetero functionalities selected from the group consistingof —O—, —NH, —N(C₁-C₆alkyl)-, —NCO(C₁-C₆alkyl)-,—NCO(C₃-C₈cycloalkyl)-N(aryl)-, —N(aryl-C₁-C₆alkyl-)-,—N(substituted-aryl-C₁-C₆alkyl-)-, —N(heteroaryl)-,—N(heteroaryl-C₁-C₆alkyl-)-, —N(substituted-heteroaryl-C₁-C₆alkyl-)-,and —S— or S(O)_(q)—, wherein q is 1 or 2 and the 3-10 memberedheterocycle ring is optionally substituted with one or moresubstituents; or a pharmaceutically acceptable salt, solvate or prodrugthereof.

In certain embodiments are provided compounds of Formula (I) or atherapeutically acceptable salt thereof wherein R₁, R₂, R₃ areindependently selected from a group consisting of hydrogen, alkyl, andhalogen; R₄ is hydrogen and R₅ is selected from the group consistinghydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene,and (NR_(A)R_(B))alkylene; R_(A), and R_(B) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, andalkylcarbonyl; or R_(A) and R_(B) taken together with the atom to whichthey are attached form a 3-10 membered heterocycle ring optionallyhaving one to three heteroatoms or hetero functionalities selected fromthe group consisting of —O—, —NH, —N(C₁-C₆-alkyl)-, —NCO(C₁-C₆-alkyl)-,—N(aryl)-, —N(aryl-C₁-C₆-alkyl-)-, —N(substituted-aryl-C₁-C₆-alkyl-)-,—N(heteroaryl)-, —N(heteroaryl-C₁-C₆-alkyl-)-,—N(substituted-heteroaryl-C₁-C₆-alkyl-)-, and —S— or S(O)_(q)—, whereinq is 1 or 2 and the 3-10 membered heterocycle ring is optionallysubstituted with one or more substituents.

In one embodiment is a compound of Formula (I) wherein Y is an arylgroup. In another embodiment the aryl group is a phenyl group. In yetanother embodiment the phenyl group is substituted with at least one R₆selected from Br, Cl, F, or I. In one embodiment R₆ is F. In oneembodiment the phenyl group is substituted with at least one R₆ selectedfrom (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment R₆ is(NR_(A)R_(B))C₁-C₆alkylene. In another embodiment C₁-C₆alkyl is selectedfrom methylene, ethylene, n-propylene, iso-propylene, n-butylene,iso-butylene, and tert-butylene. In yet another embodiment C₁-C₆alkyl ismethylene. In yet a further embodiment R_(A) and R_(B) are eachindependently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In oneembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodimentC₁-C₆alkyl is methyl. In another embodiment C₁-C₆alkyl is ethyl. In yetanother embodiment C₃-C₈cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. In a further embodiment C₃-C₈cycloalkyl iscyclopropyl. In yet a further embodiment R₆ is hydroxyalkylene. In oneembodiment hydroxyalkylene is selected from CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH₂CH(OH)CH₃, and CH₂CH₂CH₂CH₂OH.In another embodiment R_(A) and R_(B) taken together with the nitrogento which they are attached form a 6 membered heterocycle ring having 1heteroatom or hetero functionality selected from the group consisting of—O—, —NH, or —N(C₁-C₆alkyl). In yet another embodiment the heterofunctionality is —N(C₁-C₆alkyl). In a further embodiment C₁-C₆alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl. In oneembodiment Y is a heteroaryl group optionally substituted with at leastone R₆. In another embodiment the heteroaryl group is selected fromfuran, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole,pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole,benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine,thienothiophene, quinoxaline, quinoline, and isoquinoline. In yetanother embodiment the heteroaryl group is imidazole. In a furtherembodiment imidazole is substituted with C₁-C₆alkyl selected frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In yet a further embodiment C₁-C₆alkyl is methyl. In one embodiment theheteroaryl group is furan. In another embodiment the heteroaryl group isthiazole. In yet another embodiment the heteroaryl group is1,3,4-oxadiazole. In a further embodiment heteroaryl group issubstituted with C₁-C₆alkyl selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is methyl. In one embodiment Z is an aryl group.In another embodiment the aryl group is a phenyl group. In yet anotherembodiment the phenyl group is substituted with at least one R₆ selectedfrom Br, Cl, F, or I. In a further embodiment R₆ is F. In yet a furtherembodiment R₆ is C₁. In one embodiment the phenyl group is substitutedwith at least one R₆ selected from (NR_(A)R_(B))C₁-C₆alkylene,(NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,(NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene. In anotherembodiment R₆ is (NR_(A)R_(B))C₁-C₆alkylene. In yet another embodimentC₁-C₆alkyl is selected from methylene, ethylene, n-propylene,iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet afurther embodiment C₁-C₆alkyl is methylene. In a further embodimentR_(A) and R_(B) are each independently hydrogen, C₁-C₆alkyl, orC₃-C₈cycloalkyl. In one embodiment C₁-C₆alkyl is selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. Inanother embodiment C₁-C₆alkyl is methyl. In yet another embodiment R_(A)and R_(B) taken together with the nitrogen to which they are attachedform a 6 membered heterocycle ring having 1 heteroatom or heterofunctionality selected from the group consisting of —O—, —NH, or—N(C₁-C₆alkyl). In a further embodiment the hetero functionality is—N(C₁-C₆alkyl). In one embodiment C₁-C₆alkyl is selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yeta further embodiment C₁-C₆alkyl is methyl. In one embodiment Z is aheteroaryl group optionally substituted with at least one R₆. In anotherembodiment the heteroaryl group is selected from furan, pyridine,pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole,triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene,benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene,quinoxaline, quinoline, and isoquinoline. In yet another embodiment theheteroaryl group is imidazole. In a further embodiment imidazole issubstituted with C₁-C₆alkyl selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is methyl. In one embodiment the heteroaryl groupis furan. In another embodiment the heteroaryl group is thiazole. In yetanother embodiment the heteroaryl group is 1,3,4-oxadiazole. In afurther embodiment heteroaryl group is substituted with C₁-C₆alkylselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl. Inanother embodiment R₂ is hydrogen. In yet another embodiment R₂ isselected from F, Cl, Br, and I. In a further embodiment R₂ is F.

In one embodiment is a compound of Formula (I) wherein A is hydrogen. Inanother embodiment A is C₁-C₆alkyl. In a further embodiment, A isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl,and n-hexyl are optionally substituted with OH, NO₂, CN, Br, Cl, F, andI. In a further embodiment A is methyl. In yet another embodiment, A isselected from F, Cl, Br, and I. In another embodiment, A isC₃-C₈cycloalkyl. In another embodiment, A is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH,NO₂, or CN. In a further embodiment, B is C₁-C₆alkyl. In a furtherembodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet anotherembodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH,NO₂, CN, Br, Cl, F, and I. In one embodiment is a compound of Formula(I) wherein B is hydrogen. In a further embodiment B is methyl. In yetanother embodiment, B is selected from F, Cl, Br, and I. In anotherembodiment, B is C₃-C₈cycloalkyl. In another embodiment, B iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment,A is substituted with OH, NO₂, or CN. In a further embodiment, is acompound of Formula (I) wherein A is hydrogen and B is selected from Br,Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In another embodiment, is acompound of Formula (I) wherein B is hydrogen and A is selected from Br,Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In yet another embodiment,both A and B are hydrogen. In a further embodiment, both A and B areselected from Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy,alkoxyalkyl wherein C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl areoptionally substituted with at least one substituent selected from OH,NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl.

In one embodiment is a compound of Formula (II) wherein Y is an arylgroup. In another embodiment the aryl group is a phenyl group. In yetanother embodiment the phenyl group is substituted with at least one R₆selected from Br, Cl, F, or I. In one embodiment R₆ is F. In oneembodiment the phenyl group is substituted with at least one R₆ selectedfrom (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment R₆ is(NR_(A)R_(B))C₁-C₆alkylene. In another embodiment C₁-C₆alkyl is selectedfrom methylene, ethylene, n-propylene, iso-propylene, n-butylene,iso-butylene, and tert-butylene. In yet another embodiment C₁-C₆alkyleneis methylene. In yet a further embodiment R_(A) and R_(B) are eachindependently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In oneembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodimentC₁-C₆alkyl is methyl. In another embodiment C₁-C₆alkyl is ethyl. In yetanother embodiment C₃-C₈cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. In a further embodiment C₃-C₈cycloalkyl iscyclopropyl. In yet a further embodiment R₆ is hydroxyalkylene. In oneembodiment hydroxyalkylene is selected from CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH₂CH(OH)CH₃, and CH₂CH₂CH₂CH₂OH.In another embodiment R_(A) and R_(B) taken together with the nitrogento which they are attached form a 6 membered heterocycle ring having 1heteroatom or hetero functionality selected from the group consisting of—O—, —NH, or —N(C₁-C₆alkyl). In yet another embodiment the heterofunctionality is —N(C₁-C₆alkyl). In a further embodiment C₁-C₆alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl. In oneembodiment Y is a heteroaryl group optionally substituted with at leastone R₆. In another embodiment the heteroaryl group is selected fromfuran, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole,pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole,benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine,thienothiophene, quinoxaline, quinoline, and isoquinoline. In yetanother embodiment the heteroaryl group is imidazole. In a furtherembodiment imidazole is substituted with C₁-C₆alkyl selected frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In yet a further embodiment C₁-C₆alkyl is methyl. In one embodiment theheteroaryl group is furan. In another embodiment the heteroaryl group isthiazole. In yet another embodiment the heteroaryl group is1,3,4-oxadiazole. In a further embodiment heteroaryl group issubstituted with C₁-C₆alkyl selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is methyl. In one embodiment Z is an aryl group.In another embodiment the aryl group is a phenyl group. In yet anotherembodiment the phenyl group is substituted with at least one R₆ selectedfrom Br, Cl, F, or I. In a further embodiment R₆ is F. In yet a furtherembodiment R₆ is Cl. In one embodiment the phenyl group is substitutedwith at least one R₆ selected from (NR_(A)R_(B))C₁-C₆alkylene,(NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,(NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene. In anotherembodiment R₆ is (NR_(A)R_(B))C₁-C₆alkylene. In yet another embodimentC₁-C₆alkylene is selected from methylene, ethylene, n-propylene,iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet afurther embodiment C₁-C₆alkyl is methylene. In a further embodimentR_(A) and R_(B) are each independently hydrogen, C₁-C₆alkyl, orC₃-C₈cycloalkyl. In one embodiment C₁-C₆alkyl is selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. Inanother embodiment C₁-C₆alkyl is methyl. In yet another embodiment R_(A)and R_(B) taken together with the nitrogen to which they are attachedform a 6 membered heterocycle ring having 1 heteroatom or heterofunctionality selected from the group consisting of —O—, —NH, or—N(C₁-C₆alkyl). In a further embodiment the hetero functionality is—N(C₁-C₆alkyl). In one embodiment C₁-C₆alkyl is selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yeta further embodiment C₁-C₆alkyl is methyl. In another embodiment R₂ ishydrogen. In yet another embodiment R₂ is selected from F, Cl, Br, andI. In a further embodiment R₂ is F.

In one embodiment is a compound of Formula (II) wherein A is hydrogen.In another embodiment A is C₁-C₆alkyl. In a further embodiment, A isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl,and n-hexyl are optionally substituted with OH, NO₂, CN, Br, Cl, F, andI. In a further embodiment A is methyl. In yet another embodiment, A isselected from F, Cl, Br, and I. In another embodiment, A isC₃-C₈cycloalkyl. In another embodiment, A is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH,NO₂, or CN. In one embodiment is a compound of Formula (II) wherein B ishydrogen. In a further embodiment, B is C₁-C₆alkyl. In a furtherembodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet anotherembodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH,NO₂, CN, Br, Cl, F, and I. In a further embodiment B is methyl. In yetanother embodiment, B is selected from F, Cl, Br, and I. In anotherembodiment, B is C₃-C₈cycloalkyl. In another embodiment, B iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment,A is substituted with OH, NO₂, or CN. In a further embodiment, is acompound of Formula (II) wherein A is hydrogen and B is selected fromBr, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In another embodiment, is acompound of Formula (II) wherein B is hydrogen and A is selected fromBr, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In yet another embodiment,both A and B are hydrogen. In a further embodiment, both A and B areselected from Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy,alkoxyalkyl wherein C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl areoptionally substituted with at least one substituent selected from OH,NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl.

In yet a further aspect is a compound selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet another aspect is a compound selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet another aspect is a compound selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof

In yet a further embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In yet a further embodiment is a compound selected from:

-   (8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,    and-   (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I) and Formula (II) or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug and a pharmaceutically acceptable carrier, excipient, binder ordiluent thereof.

In one aspect is a method of inhibiting poly(ADP-ribose)polymerase(PARP) in a subject in need of PARP inhibition comprising administeringto the subject a therapeutically effective amount of a compound ofFormula (I) and Formula (II).

In another aspect is a method of treating a disease ameliorated by theinhibition of PARP comprising administering to a subject in need oftreatment a therapeutically effective amount of a compound of Formula(I) and Formula (II).

In one embodiment the disease is selected from the group consisting of:vascular disease; septic shock; ischaemic injury; reperfusion injury;neurotoxicity; hemorrhagic shock; inflammatory diseases; multiplesclerosis; secondary effects of diabetes; and acute treatment ofcytoxicity following cardiovascular surgery.

In another aspect is a method of treating cancer, comprisingadministering to a subject in need of treatment a therapeuticallyeffective amount of a compound of Formula (I) and Formula (II) incombination with ionizing radiation, one or more chemotherapeuticagents, or a combination thereof.

In one embodiment the compound of Formula (I) and Formula (II) isadministered simultaneously with ionizing radiation, one or morechemotherapeutic agents, or a combination thereof. In another embodimentthe compound of Formula (I) and Formula (II) is administeredsequentially with ionizing radiation, one or more chemotherapeuticagents, or a combination thereof.

In yet another aspect is a method of treating a cancer deficient inHomologous Recombination (HR) dependent DNA double strand break (DSB)repair pathway, comprising administering to a subject in need oftreatment a therapeutically effective amount of a compound of Formula(I) and Formula (II).

In one embodiment the cancer comprises one or more cancer cells having areduced or abrogated ability to repair DNA DSB by HR relative to normalcells. In another embodiment the cancer cells have a BRCA1 or BRCA2deficient phenotype. In yet another embodiment the cancer cells aredeficient in BRCA1 or BRCA2. In a further embodiment the subject isheterozygous for a mutation in a gene encoding a component of the HRdependent DNA DSB repair pathway. In yet a further embodiment thesubject is heterozygous for a mutation in BRCA1 and/or BRCA2. In oneembodiment the cancer is breast, ovarian, pancreatic or prostate cancer.In another embodiment the treatment further comprises administration ofionizing radiation or a chemotherapeutic agent.

In one aspect is the use of a compound of Formula (I) and Formula (II)in the formulation of a medicament for the treatment of apoly(ADP-ribose)polymerase mediated disease or condition.

In another aspect is an article of manufacture, comprising packagingmaterial, a compound of Formula (I) and Formula (II), and a label,wherein the compound is effective for modulating the activity of theenzyme poly(ADP-ribose)polymerase, or for treatment, prevention oramelioration of one or more symptoms of apoly(ADP-ribose)polymerase-dependent orpoly(ADP-ribose)polymerase-mediated disease or condition, wherein thecompound is packaged within the packaging material, and wherein thelabel indicates that the compound, or pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, or a pharmaceutical composition comprising such acompound is used for modulating the activity ofpoly(ADP-ribose)polymerase, or for treatment, prevention or ameliorationof one or more symptoms of a poly(ADP-ribose)polymerase-dependent orpoly(ADP-ribose)polymerase-mediated disease or condition.

DETAILED DESCRIPTION OF THE INVENTION

PARP has an essential role in facilitating DNA repair, controlling RNAtranscription, mediating cell death, and regulating immune response.PARP inhibitors demonstrate efficacy in numerous models of diseaseparticularly in models of ischemia reperfusion injury, inflammatorydisease, degenerative diseases, protection from above adverse effects ofcytotoxic compounds, and potentiation of cytotoxic cancer therapy. Theyare efficacious in the prevention of ischemia reperfusion injury inmodels of myocardial infarction, stoke, other neural trauma, organtransplantation, as well as reperfusion of the eye, kidney, gut andskeletal muscle. Inhibitors are efficacious in inflammatory diseasessuch as arthritis, gout, inflammatory bowel disease, CNS inflammationsuch as MS and allergic encephalitis, sepsis, septic shock, hemorrhagicshock, pulmonary fibrosis, and uveitis. PARP inhibitors also showbenefit in several models of degenerative disease including diabetes andParkinson's disease. PARP inhibitors ameliorate the liver toxicityfollowing acetaminophen overdose, cardiac and kidney toxicities fromdoxorubicin and platinum based antineoplastic agents, as well as skindamage secondary to sulfur mustards. In various cancer models, PARPinhibitors are shown to potentiate radiation and chemotherapy byincreasing apoptosis of cancer cells, limiting tumor growth, decreasingmetastasis, and prolonging the survival of tumor-bearing animals.

In certain embodiments are provided compounds of Formula (I)

or a therapeutically acceptable salt thereof wherein R₁, R₂, and R₃ areeach independently selected from the group consisting of hydrogen,halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl,cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro,NR_(A)R_(B), NR_(A)R_(B)alkylene, and (NR_(A)R_(B))carbonyl;R_(A), and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R_(A) and R_(B) takentogether with the atom to which they are attached form a 3-10 memberedheterocycle ring optionally having one to three heteroatoms or heterofunctionalities selected from the group consisting of —O—, —NH,—N(C₁-C₆-alkyl)-, —N(aryl)-, alkyl-)-,—N(substituted-aryl-C₁-C₆-alkyl-)-, —N(heteroaryl)-,—N(heteroaryl-C₁-C₆-alkyl-)-, —N(substituted-heteroaryl-C₁-C₆-alkyl-)-,and —S— or S(O)_(q)—, wherein q is 1 or 2 and the 3-10 memberedheterocycle ring is optionally substituted with one or moresubstituents; R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,hydroxyalkylene, and (NR_(A)R_(B))alkylene;A and B are each independently selected from hydrogen, Br, Cl, F, I, OH,C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH;Y and Z are each independently selected from the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3        substituents R₆; R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3        substituents R₆; R₆ is previously as defined;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene; or a        pharmaceutically acceptable salt, solvate or prodrug thereof.

In certain embodiments are provided compounds of Formula (I) or atherapeutically acceptable salt thereof wherein R₁, R₂, R₃ areindependently selected from a group consisting of hydrogen, alkyl, andhalogen; R₄ is hydrogen and R₅ is selected from the group consistinghydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene,and (NR_(A)R_(B))alkylene; R_(A), and R_(B) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, andalkylcarbonyl; or R_(A) and R_(B) taken together with the atom to whichthey are attached form a 3-10 membered heterocycle ring optionallyhaving one to three heteroatoms or hetero functionalities selected fromthe group consisting of —O—, —NH, —N(C₁-C₆-alkyl)-, —NCO(C₁-C₆-alkyl)-,—N(aryl)-, —N(aryl-C₁-C₆-alkyl-)-, —N(substituted-aryl-C₁-C₆-alkyl-)-,—N(heteroaryl)-, —N(heteroaryl-C₁-C₆-alkyl-)-,—N(substituted-heteroaryl-C₁-C₆-alkyl-)-, and —S— or S(O)_(q)—, whereinq is 1 or 2 and the 3-10 membered heterocycle ring is optionallysubstituted with one or more substituents; A and B are eachindependently selected from hydrogen, Br, Cl, F, I, OH, C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH; Y and Z are eachindependently selected from the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3 R₆;        wherein each R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3 R₆;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene; or a        pharmaceutically acceptable salt, solvate or prodrug thereof.

In certain embodiments are provided compounds of Formula (I) or atherapeutically acceptable salt thereof wherein R₁, R₂, and R₃ areindependently selected from a group consisting of hydrogen, alkyl, andhalogen; R₄ and R₅ are hydrogen; R_(A) and R_(B) are independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl, andalkylcarbonyl; or R_(A) and R_(B) taken together with the atom to whichthey are attached form a 3-10 membered heterocycle ring optionallyhaving one to three heteroatoms or hetero functionalities selected fromthe group consisting of —O—, —NH, —N(C₁-C₆-alkyl)-, —NCO(C₁-C₆-alkyl)-,—N(aryl)-, —N(aryl-C₁-C₆-alkyl-)-, —N(substituted-aryl-C₁-C₆-alkyl-)-,—N(heteroaryl)-, —N(heteroaryl-C₁-C₆-alkyl-)-,—N(substituted-heteroaryl-C₁-C₆-alkyl-)-, and —S— or S(O)_(q)—, whereinq is 1 or 2 and the 3-10 membered heterocycle ring is optionallysubstituted with one or more substituents; A and B are eachindependently selected from hydrogen, Br, Cl, F, I, C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl; Y and Z are each independently selectedfrom the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3 R₆;        wherein each R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3 R₆;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene; or a        pharmaceutically acceptable salt, solvate or prodrug thereof.

In certain embodiments are provided compounds of Formula (I) or atherapeutically acceptable salt thereof wherein R₁, R₂, R₃, R₄ and R₅are hydrogen; R_(A), and R_(B) are independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R_(A)and R_(B) taken together with the atom to which they are attached form a3-10 membered heterocycle ring optionally having one to threeheteroatoms or hetero functionalities selected from the group consistingof —O—, —NH, —N(C₁-C₆-alkyl)-, —NCO(C₁-C₆-alkyl)-, —N(aryl)-,—N(aryl-C₁-C₆-alkyl-)-, —N(substituted-aryl-C₁-C₆-alkyl-)-,—N(heteroaryl)-, —N(heteroaryl-C₁-C₆-alkyl-)-,—N(substituted-heteroaryl-C₁-C₆-alkyl-)-, and —S— or S(O)_(q)—, whereinq is 1 or 2 and the 3-10 membered heterocycle ring is optionallysubstituted with one or more substituents; A and B are eachindependently selected from hydrogen, Br, Cl, F, I, OH, C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH; Y and Z are eachindependently selected from the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3 R₆;        wherein each R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3 R₆;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene; or a        pharmaceutically acceptable salt, solvate or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein R₁, R₂, R₃ areeach independently selected from a group consisting of hydrogen, alkyl,and halogen; R₄ is hydrogen and R₅ is selected from the group consistinghydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene,and (NR_(A)R_(B))alkylene; and isomers, salts, solvates, chemicallyprotected forms, and prodrugs thereof.

In another embodiment is a compound of Formula (I) wherein R₁, R₂, R₃are each independently selected from a group consisting of hydrogen,alkyl, and halogen; R₄ and R₅ are hydrogen; and isomers, salts,solvates, chemically protected forms, and prodrugs thereof.

In a further embodiment is a compound of Formula (I) wherein R₁, R₂, R₃,R₄ are each hydrogen and R₅ is alkyl.

In yet another embodiment is a compound of Formula (I) wherein R₁, R₂,R₃, R₄ are each hydrogen; and R₅ is methyl.

In one embodiment is a compound of Formula (I) wherein R₁, R₂, and R₃are each hydrogen.

In another embodiment is a compound of Formula (I) wherein Y and Z areeach independently selected from the group consisting of:

-   -   a) a phenyl group optionally substituted with 1, 2, or 3 R₆;    -   b) a pyridyl group optionally substituted with 1, 2, or 3 R₆;        and    -   c) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))carbonylalkylene.

In a further embodiment is a compound of Formula (I) wherein Y and Z areeach independently selected from the group consisting of

-   -   a) a phenyl group optionally substituted with 1, 2, or 3 R₆;    -   b) a imidazole group optionally substituted with 1, 2, or 3 R₆;        and    -   c) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene        (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))carbonylalkylene.

In a further embodiment is a compound of Formula (I) wherein Y and Z areeach independently selected from the group consisting of

-   -   d) a phenyl group optionally substituted with 1, 2, or 3 R₆;    -   e) a triazole group optionally substituted with 1, 2, or 3 R₆;        and    -   f) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene        (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))carbonylalkylene.

In one embodiment is a compound of Formula (I) wherein R₅ is hydrogen oran alkyl group. In another embodiment, R₅ is hydrogen. In a furtherembodiment, R₅ is C₁-C₆ alkyl. In yet a further embodiment, R₅ is CH₃.In another embodiment, R₅ is CH₂CH₃.

In another embodiment is a compound of Formula (I) wherein R₄ ishydrogen or an alkyl group. In yet another embodiment, R₄ is hydrogen.

In one embodiment, R₂ is selected from the group consisting of hydrogen,halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl,cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro,NR_(A)R_(B), NR_(A)R_(B)alkylene, and (NR_(A)R_(B))carbonyl. In afurther embodiment R₂ is a halogen selected from F, Cl, Br, and I. Inyet a further embodiment, R₂ is fluorine. In one embodiment, R₂ ishydrogen.

In another embodiment, R₃ is selected from the group consisting ofhydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl,alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro,NR_(A)R_(B), NR_(A)R_(B)alkylene, and (NR_(A)R_(B))carbonyl. In afurther embodiment, R₃ is hydrogen. In some embodiments, R₁ is selectedfrom the group consisting of hydrogen, halogen, alkenyl, alkoxy,alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy,haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR_(A)R_(B),NR_(A)R_(B)alkylene, and (NR_(A)R_(B))carbonyl. In a further embodiment,R₁ is hydrogen.

Also disclosed herein are compounds of Formula (I) wherein Z is an arylgroup optionally substituted with 1, 2, or 3 R₆; wherein each R₆ isselected from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₂-C₈heterocycloalkyl; C₂-C₆alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo,heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio,heteroarylalkylthio, heterocycloalkoxy, C₂-C₈heterocycloalkylthio,heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment is a compound ofFormula (I) wherein Z is an optionally substituted phenyl group. In oneembodiment, Z is a phenyl group. In another embodiment, the phenyl groupis optionally substituted with at least one R₆ selected from OH, NO₂,CN, Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,C₂-C₆alkynyl, aryl, arylalkyl, C₃-C₈cycloalkylalkyl, haloalkoxy,haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy,heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In another embodiment, R₆ is(NR_(A)R_(B))alkylene. In a further embodiment, R₆ is CH₂(NR_(A)R_(B)).In a further embodiment, R₆ is CH₂(NR_(A)R_(B)) wherein NR_(A)R_(B) isazetidine, pyrrolidine, piperidine or morpholine. In yet a furtherembodiment, R_(A) is H or alkyl. In another embodiment, R_(A) isC₁-C₆alkyl. In yet another embodiment, R_(A) is CH₃. In anotherembodiment, R_(B) is H or alkyl. In one embodiment, R_(B) is C₁-C₆alkyl.In yet another embodiment, R_(B) is CH₃. In a further embodiment, R₆ isCH₂NHCH₃. In yet a further embodiment, R₆ is CH₂NCH₃CH₃. In oneembodiment, R₆ is (C═O)heterocycloalkyl(C═O)alkyl. In one embodiment R₆is (C═O)heterocycloalkyl(C═O)alkyl wherein the heterocycloalkyl grouphas at least one heteroatom selected from O, N, and S. In anotherembodiment, the heterocycloalkyl group has two N atoms. In a furtherembodiment, R₆ is (C═O)heterocycloalkyl(C═O)alkyl wherein alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl,iso-butyl, and t-butyl. In one embodiment, the alkyl group iscyclopropyl. In another embodiment, the alkyl group is iso-propyl. Inone embodiment, R₆ is

In another embodiment, R₆ is

Presented herein are compounds of Formula (I) wherein Z is an optionallysubstituted heteroaryl group. In one embodiment, the heteroaryl group isselected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole,thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, pyridazine,1,3,5-trazine, 1,2,4-triazine, quinoxaline, benzimidazole,benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole,imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine,isoindole, indole, indazole, isoquinoline, quinoline, phthalazine,naphthyridine, quinazoline, cinnoline, and pteridine. In one embodiment,Z is pyridine. In another embodiment, Z is optionally substitutedpyridine.

Also disclosed herein are compounds of Formula (I) wherein Y is an arylgroup optionally substituted with 1, 2, or 3 R₆; wherein each R₆ isselected from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₂-C₈heterocycloalkyl; C₂-C₆alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo,heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio,heteroarylalkylthio, heterocycloalkoxy, C₂-C₈heterocycloalkylthio,heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment is a compound ofFormula (I) wherein Y is an optionally substituted phenyl group. In oneembodiment, Y is a phenyl group. In another embodiment, the phenyl groupis optionally substituted with at least one R₆ selected from OH, NO₂,CN, Br, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,C₂-C₆alkynyl, aryl, arylalkyl, C₃-C₈cycloalkylalkyl, haloalkoxy,haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy,heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In a further embodiment, R₆ isCH₂(NR_(A)R_(B)). In yet a further embodiment, R_(A) is H or alkyl. Inanother embodiment, R_(A) is C₁-C₆alkyl. In yet another embodiment,R_(A) is CH₃. In another embodiment, R_(B) is H or alkyl. In oneembodiment, R_(B) is C₁-C₆alkyl. In yet another embodiment, R_(B) isCH₃. In a further embodiment, R₆ is CH₂NHCH₃. In yet a furtherembodiment, R₆ is CH₂NCH₃CH₃. In one embodiment, R₆ is(C═O)heterocycloalkyl(C═O)alkyl. In one embodiment R₆ is(C═O)heterocycloalkyl(C═O)alkyl wherein the heterocycloalkyl group hasat least one heteroatom selected from O, N, and S. In anotherembodiment, the heterocycloalkyl group has two N atoms. In a furtherembodiment, R₆ is (C═O)heterocycloalkyl(C═O)alkyl wherein alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl,iso-butyl, and t-butyl. In one embodiment, the alkyl group iscyclopropyl. In another embodiment, the alkyl group is iso-propyl. Inone embodiment, R₆ is

In another embodiment, R₆ is

Presented herein are compounds of Formula (I) wherein Y is an optionallysubstituted heteroaryl group. In one embodiment, the heteroaryl group isselected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole,thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, pyridazine,1,3,5-trazine, 1,2,4-triazine, quinoxaline, benzimidazole,benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole,imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine,isoindole, indole, indazole, isoquinoline, quinoline, phthalazine,naphthyridine, quinazoline, cinnoline, and pteridine. In one embodiment,Y is pyridine. In another embodiment, Y is optionally substitutedpyridine. In one embodiment, Y is imidazole. In another embodiment, Y isoptionally substituted imidazole. In one embodiment, Y is triazole. Inanother embodiment, Y is optionally substituted triazole.

In one embodiment, Y is a substituent independently selected from thegroup consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,(NR_(A)R_(B))alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment, Y is alkyl. In anotherembodiment, Y is C₁-C₆ alkyl. In a further embodiment, Y is selectedfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl ortert-butyl. In another embodiment, Y is iso-propyl.

Also disclosed herein are compounds of Formula (I) wherein Y is anoptionally substituted heterocycloalkyl group. In one embodiment, theheterocycloalkyl group is selected from pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. In another embodiment the heterocycloalkyl group isselected from pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl,pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,1,3-oxathiolanyl, indolinyl, isoindolinyl, morpholinyl, and pyrazolinyl.In another embodiment, the heterocycloalkyl group is piperidinyl.

In another aspect is a compound of Formula (IA):

or a therapeutically acceptable salt, solvate or prodrug thereof whereinR₁, R₂, and R₃ are each independently selected from the group consistingof hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl,cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,hydroxyalkylene, nitro, NR_(A)R_(B), NR_(A)R_(B)alkylene, and(NR_(A)R_(B))carbonyl;R_(A), and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R_(A) and R_(B) takentogether with the atom to which they are attached form a 3-10 memberedheterocycle ring optionally having one to three heteroatoms or heterofunctionalities selected from the group consisting of —O—, —NH,—N(C₁-C₆-alkyl)-, —NCO(C₁-C₆-alkyl)-, —N(aryl)-, —N(aryl-C₁-C₆-alkyl-)-,—N(substituted-aryl-C₁-C₆-alkyl-)-, —N(heteroaryl)-,—N(heteroaryl-C₁-C₆-alkyl-)-, —N(substituted-heteroaryl-C₁-C₆-alkyl-)-,and —S— or S(O)_(q)—, wherein q is 1 or 2 and the 3-10 memberedheterocycle ring is optionally substituted with one or moresubstituents; R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,hydroxyalkylene, and (NR_(A)R_(B))alkylene;A and B are each independently selected from hydrogen, Br, Cl, F, I, OH,C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH;Y is selected from the group consisting of:

-   -   a) an aryl group optionally substituted with 1, 2, or 3        substituents R₆; R₆ is selected from OH, NO₂, CN, Br, Cl, F, I,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl;        C₂-C₆alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl, arylalkyl,        C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,        oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,        heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,        C₂-C₈heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   b) a heteroaryl group optionally substituted with 1, 2, or 3        substituents R₆; R₆ is selected independently from the group        consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl,        cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl,        halogen, hydroxyl, hydroxyalkylene, nitro, oxo, heteroaryl,        heteroarylalkoxy, heteroaryloxy, heteroarylthio,        heteroarylalkylthio, heterocycloalkyl, heterocycloalkoxy,        heterocycloalkylthio, heterocyclooxy, heterocyclothio,        NR_(A)R_(B), (NR_(A)R_(B))alkylene, (NR_(A)R_(B))carbonyl,        (NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and        (NR_(A)R_(B))sulfonylalkylene;    -   c) a substituent independently selected from the group        consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,        cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, (NR_(A)R_(B))alkylene,        (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkylene,        (NR_(A)R_(B))sulfonyl, and (NR_(A)R_(B))sulfonylalkylene; and    -   n is an integer from 0-4; or a pharmaceutically acceptable salt,        solvate or prodrug thereof.

In another embodiment is a compound of Formula (IA) having thestructure:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (IA) wherein Y is an arylgroup. In another embodiment, Y is a heteroaryl group. In a furtherembodiment, the aryl group is a phenyl group. In yet a furtherembodiment is a compound of Formula (IA) wherein the phenyl group issubstituted with at least one R₆. In yet another embodiment the phenylgroup is substituted with at least one R₆ selected from Br, Cl, F, or I.In one embodiment R₆ is F. In one embodiment is a compound of Formula(IA) wherein the phenyl group is substituted with at least one R₆selected from (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment R₆ is(NR_(A)R_(B))C₁-C₆alkylene. In another embodiment C₁-C₆alkylene isselected from methylene, ethylene, n-propylene, iso-propylene,n-butylene, iso-butylene, and tert-butylene. In yet another embodimentC₁-C₆alkylene is methylene. In yet a further embodiment R_(A) and R_(B)are each independently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In oneembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodimentC₁-C₆alkyl is methyl. In another embodiment C₁-C₆alkyl is ethyl. In oneembodiment is a compound of Formula (IA) wherein C₃-C₈cycloalkyl iscyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In a furtherembodiment C₃-C₈cycloalkyl is cyclopropyl. In one embodiment is acompound of Formula (IA) wherein R₆ is hydroxyalkylene. In oneembodiment hydroxyalkylene is selected from CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH₂CH(OH)CH₃, and CH₂CH₂CH₂CH₂OH.In another embodiment R_(A) and R_(B) taken together with the nitrogento which they are attached form a 6 membered heterocycle ring having 1heteroatom or hetero functionality selected from the group consisting of—O—, —NH, or —N(C₁-C₆alkyl). In yet another embodiment the heterofunctionality is —N(C₁-C₆alkyl). In a further embodiment C₁-C₆alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl.

In one embodiment is a compound of Formula (IA) wherein Y is aheteroaryl group optionally substituted with at least one R₆. In anotherembodiment the heteroaryl group is selected from furan, pyridine,pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole,triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene,benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene,quinoxaline, quinoline, and isoquinoline. In yet another embodiment theheteroaryl group is imidazole. In a further embodiment imidazole issubstituted with C₁-C₆alkyl selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is methyl. In one embodiment the heteroaryl groupis furan. In another embodiment the heteroaryl group is thiazole. In yetanother embodiment the heteroaryl group is 1,3,4-oxadiazole. In afurther embodiment heteroaryl group is substituted with C₁-C₆alkylselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl.

In one embodiment is a compound of Formula (IA) wherein A and B are eachindependently selected from hydrogen, Br, Cl, F, I, OH, C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl and B is not OH.

In yet another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein Y is a heteroarylgroup selected from furan, pyridine, pyrimidine, pyrazine, imidazole,thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole,isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole,benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine,thienothiophene, quinoxaline, quinoline, and isoquinoline. In anotherembodiment, Y is an imidazole group. In yet another embodiment, theimidazole group is substituted with a C₁-C₆alkyl group. In anotherembodiment, the C₁-C₆alkyl group is methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, and tert-butyl. In a further embodiment C₁-C₆alkylis methyl. In another embodiment is a compound of Formula (I) wherein Yis a substituted imidazole group and Z is selected from an aryl group ora heteroaryl group. In a further embodiment, Z is an aryl group. In yeta further embodiment, the aryl group is a phenyl group. In yet a furtherembodiment, the aryl group is a phenyl group substituted by a halogen.In yet a further embodiment Z is a heteroaryl group. In anotherembodiment, the heteroaryl group is furan, pyridine, pyrimidine,pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole,thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, andisoquinoline. In a further embodiment, the heteroaryl group isimidazole. In another embodiment, the imidazole group is substitutedwith a C₁-C₆alkyl group. In another embodiment, the C₁-C₆alkyl group ismethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In a further embodiment C₁-C₆alkyl is methyl.

In another embodiment is a compound of Formula (I) wherein Y is atriazole group. In yet another embodiment, the triazole group issubstituted with a C₁-C₆alkyl group. In another embodiment, theC₁-C₆alkyl group is methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, and tert-butyl. In a further embodiment C₁-C₆alkyl is methyl.In another embodiment is a compound of Formula (I) wherein Y is asubstituted triazole group and Z is selected from an aryl group or aheteroaryl group. In a further embodiment, Z is an aryl group. In yet afurther embodiment, the aryl group is a phenyl group. In yet a furtherembodiment, the aryl group is a phenyl group substituted by a halogen.In yet a further embodiment Z is a heteroaryl group. In anotherembodiment, the heteroaryl group is furan, pyridine, pyrimidine,pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole,thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, andisoquinoline. In a further embodiment, the heteroaryl group is triazole.In another embodiment, the triazole group is substituted with aC₁-C₆alkyl group. In another embodiment, the C₁-C₆alkyl group is methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In afurther embodiment C₁-C₆alkyl is methyl.

In another embodiment is a compound selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one aspect is a compound of Formula (II):

wherein:Y is an aryl or heteroaryl group optionally substituted with at leastone R₆;Z is an aryl group optionally substituted with at least one R₆;R₆ is selected from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl; C₂-C₆alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl,arylalkyl, C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio,heteroarylalkylthio, heterocycloalkoxy, C₂-C₈heterocycloalkylthio,heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene;R₂ is selected from hydrogen, Br, Cl, I, or F;A and B are each independently selected from hydrogen, Br, Cl, F, I, OH,C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH;R_(A), and R_(B) are independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₃-C₈cycloalkyl, and alkylcarbonyl; or R_(A) andR_(B) taken together with the atom to which they are attached form a3-10 membered heterocycle ring optionally having one to threeheteroatoms or hetero functionalities selected from the group consistingof —O—, —NH, —N(C₁-C₆alkyl)-, —NCO(C₁-C₆alkyl)-,—NCO(C₃-C₈cycloalkyl)-N(aryl)-, —N(aryl-C₁-C₆alkyl-)-,—N(substituted-aryl-C₁-C₆alkyl-)-, —N(heteroaryl)-,—N(heteroaryl-C₁-C₆alkyl-)-, —N(substituted-heteroaryl-C₁-C₆alkyl-)-,and —S— or S(O)_(q)—, wherein q is 1 or 2 and the 3-10 memberedheterocycle ring is optionally substituted with one or moresubstituents; or a pharmaceutically acceptable salt, solvate or prodrugthereof.

In one embodiment is a compound of Formula (II) wherein Y is an arylgroup. In another embodiment the aryl group is a phenyl group. In yetanother embodiment the phenyl group is substituted with at least one R₆selected from Br, Cl, F, or I. In one embodiment R₆ is F. In oneembodiment the phenyl group is substituted with at least one R₆ selectedfrom (NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In one embodiment R₆ is(NR_(A)R_(B))C₁-C₆alkylene. In another embodiment C₁-C₆alkylene isselected from methylene, ethylene, n-propylene, iso-propylene,n-butylene, iso-butylene, and tert-butylene. In yet another embodimentC₁-C₆alkylene is methylene. In yet a further embodiment R_(A) and R_(B)are each independently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In oneembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one embodimentC₁-C₆alkyl is methyl. In another embodiment C₁-C₆alkyl is ethyl. In yetanother embodiment C₃-C₈cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. In a further embodiment C₃-C₈cycloalkyl iscyclopropyl. In yet a further embodiment R₆ is hydroxyalkylene. In oneembodiment hydroxyalkylene is selected from CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH₂CH(OH)CH₃, and CH₂CH₂CH₂CH₂OH.In another embodiment R_(A) and R_(B) taken together with the nitrogento which they are attached form a 6 membered heterocycle ring having 1heteroatom or hetero functionality selected from the group consisting of—O—, —NH, or —N(C₁-C₆alkyl). In yet another embodiment the heterofunctionality is —N(C₁-C₆alkyl). In a further embodiment C₁-C₆alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl.

In one embodiment is a compound of Formula (II) wherein Y is aheteroaryl group optionally substituted with at least one R₆. In anotherembodiment the heteroaryl group is selected from furan, pyridine,pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole,triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene,benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene,quinoxaline, quinoline, and isoquinoline. In yet another embodiment theheteroaryl group is imidazole. In a further embodiment imidazole issubstituted with C₁-C₆alkyl selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is methyl. In one embodiment the heteroaryl groupis furan. In another embodiment the heteroaryl group is thiazole. In yetanother embodiment the heteroaryl group is 1,3,4-oxadiazole. In afurther embodiment heteroaryl group is substituted with C₁-C₆alkylselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In yet a further embodiment C₁-C₆alkyl is methyl.

In one embodiment is a compound of Formula (II) wherein Z is an arylgroup. In another embodiment the aryl group is a phenyl group. In yetanother embodiment the phenyl group is substituted with at least one R₆selected from Br, Cl, F, or I. In a further embodiment R₆ is F. In yet afurther embodiment R₆ is C₁. In one embodiment the phenyl group issubstituted with at least one R₆ selected from(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene. In another embodiment R₆ is(NR_(A)R_(B))C₁-C₆alkylene. In yet another embodiment C₁-C₆alkylene isselected from methylene, ethylene, n-propylene, iso-propylene,n-butylene, iso-butylene, and tert-butylene. In yet a further embodimentC₁-C₆alkylene is methylene. In a further embodiment R_(A) and R_(B) areeach independently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl. In oneembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In another embodimentC₁-C₆alkyl is methyl. In yet another embodiment R_(A) and R_(B) takentogether with the nitrogen to which they are attached form a 6 memberedheterocycle ring having 1 heteroatom or hetero functionality selectedfrom the group consisting of —O—, —NH, or —N(C₁-C₆alkyl). In a furtherembodiment the hetero functionality is —N(C₁-C₆alkyl). In one embodimentC₁-C₆alkyl is selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, and tert-butyl. In yet a further embodimentC₁-C₆alkyl is methyl. In a further embodiment, R₆ is CH₂(NR_(A)R_(B))wherein NR_(A)R_(B) is azetidine, pyrrolidine, piperidine or morpholine.In another embodiment R₂ is hydrogen. In yet another embodiment R₂ isselected from F, Cl, Br, and I. In a further embodiment R₂ is F.

In one embodiment is a compound of Formula (II) wherein A and B arehydrogen. In another embodiment A and B are independently selected fromhydrogen and C₁-C₆alkyl.

In a further embodiment is a compound of Formula (II) wherein Z is aryland Y is independently selected from the group consisting of

-   -   a) phenyl group optionally substituted with 1, 2, or 3 R₆;    -   b) a imidazole group optionally substituted with 1, 2, or 3 R₆;    -   c) a triazole group optionally substituted with 1, 2, or 3 R₆;        and    -   d) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene        (NR_(A)R_(B))carbonyl.

In a further embodiment is a compound of Formula (II) wherein Z isphenyl and Y is independently selected from the group consisting of

-   -   e) phenyl group optionally substituted with 1, 2, or 3 R₆;    -   f) a imidazole group optionally substituted with 1, 2, or 3 R₆;    -   g) a triazole group optionally substituted with 1, 2, or 3 R₆;        and    -   h) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene        (NR_(A)R_(B))carbonyl.

In a further embodiment is a compound of Formula (II) wherein Z isphenyl substituted with 1, 2, or 3 R₆ and Y is independently selectedfrom the group consisting of

-   -   i) phenyl group optionally substituted with 1, 2, or 3 R₆;    -   j) a imidazole group optionally substituted with 1, 2, or 3 R₆;    -   k) a triazole group optionally substituted with 1, 2, or 3 R₆;        and    -   l) a substituent independently selected from the group        consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,        arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,        heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, (NR_(A)R_(B))alkylene        (NR_(A)R_(B))carbonyl.

In a further embodiment, A is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. Inyet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substitutedwith OH, NO₂, CN, Br, Cl, F, and I. In a further embodiment A is methyl.In yet another embodiment, A is selected from F, Cl, Br, and I. Inanother embodiment, A is C₃-C₈cycloalkyl. In a further embodiment, A isOH. In another embodiment, A is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In one embodiment, A is substituted with OH, NO₂, or CN. Ina further embodiment, A is hydrogen. In a further embodiment, B ishydrogen. In a further embodiment, B is C₁-C₆alkyl. In a furtherembodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet anotherembodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH,NO₂, CN, Br, Cl, F, and I. In a further embodiment B is methyl. In yetanother embodiment, B is selected from F, Cl, Br, and I. In anotherembodiment, B is C₃-C₈cycloalkyl. In another embodiment, B iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment,A is substituted with OH, NO₂, or CN. In a further embodiment, is acompound of Formula (II) wherein A is hydrogen and B is selected fromBr, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In another embodiment, is acompound of Formula (II) wherein B is hydrogen and A is selected fromBr, Cl, F, I, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl whereinC₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionallysubstituted with at least one substituent selected from OH, NO₂, CN, Br,Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl. In yet another embodiment,both A and B are hydrogen. In a further embodiment, both A and B areselected from Br, Cl, F, I, OH, C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy,alkoxyalkyl wherein C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl areoptionally substituted with at least one substituent selected from OH,NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl, and C₃-C₈cycloalkyl wherein B is notOH.

Also described herein are stereoisomers of compounds of Formula (I),(IA), or (II), such as enantiomers, diastereomers, and mixtures ofenantiomers or diastereomers. In one embodiment is a stereoisomer of acompound of Formula (II) having the structures:

wherein:Y is an aryl or heteroaryl group optionally substituted with at leastone R₆;Z is an aryl group optionally substituted with at least one R₆;A and B are each independently selected from hydrogen, Br, Cl, F, I, OH,C₁-C₆alkyl, C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl wherein C₁-C₆alkyl,C₃-C₈cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with atleast one substituent selected from OH, NO₂, CN, Br, Cl, F, I,C₁-C₆alkyl, and C₃-C₈cycloalkyl, wherein B is not OH;R₆ is selected from OH, NO₂, CN, Br, Cl, F, I, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₂-C₈heterocycloalkyl; C₂-C₆alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C₂-C₆alkynyl, aryl,arylalkyl, C₃-C₈cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene,oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio,heteroarylalkylthio, heterocycloalkoxy, C₂-C₈heterocycloalkylthio,heterocyclooxy, heterocyclothio, NR_(A)R_(B),(NR_(A)R_(B))C₁-C₆alkylene, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))carbonylalkylene, (NR_(A)R_(B))sulfonyl, and(NR_(A)R_(B))sulfonylalkylene;R₂ is selected from hydrogen, Br, Cl, I, or F;R_(A), and R_(B) are independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₃-C₈cycloalkyl, and alkylcarbonyl; or R_(A) andR_(B) taken together with the atom to which they are attached form a3-10 membered heterocycle ring optionally having one to threeheteroatoms or hetero functionalities selected from the group consistingof —O—, —NH, —N(C₁-C₆alkyl)-, —NCO(C₁-C₆alkyl)-,—NCO(C₃-C₈cycloalkyl)-N(aryl)-, —N(aryl-C₁-C₆alkyl-)-,—N(substituted-aryl-C₁-C₆alkyl-)-, —N(heteroaryl)-,—N(heteroaryl-C₁-C₆alkyl-)-, —N(substituted-heteroaryl-C₁-C₆alkyl-)-,and —S— or S(O)_(q)—, wherein q is 1 or 2 and the 3-10 memberedheterocycle ring is optionally substituted with one or moresubstituents; or a pharmaceutically acceptable salt, solvate or prodrugthereof.

In one embodiment is the stereoisomer of the compound of Formula (II)shown above, having the substituents shown above, wherein R₂ isfluorine. In another embodiment is the compound of Formula (II) shownabove, having the substituents shown above, wherein Y is an imidazolegroup. In another embodiment is the compound of Formula (II) shownabove, having the substituents shown above, wherein the imidazole groupof Y is substituted with a C₁-C₆alkyl group. In a further embodiment,the C₁-C₆alkyl is methyl. In yet another embodiment is a compound ofFormula (II), shown above, having the substituents shown above, whereinY is a triazole group. In another embodiment is the compound of Formula(II) shown above, having the substituents shown above, wherein thetriazole group of Y is substituted with a C₁-C₆alkyl group. In a furtherembodiment, the C₁-C₆alkyl is methyl. In yet a further embodiment is thecompound of Formula (II) shown above, having the substituents above,wherein the Y group is an aryl group. In a further embodiment is thecompound of Formula (II) shown above, having the substituents shownabove, wherein the aryl group of Y is a phenyl group. In a furtherembodiment, the phenyl group is substituted with a halogen. In yet afurther embodiment, the halogen is F. In yet another embodiment thehalogen is selected from Br, Cl, and I. In yet another embodiment, isthe compound of Formula (II) shown above, having the substituents shownabove, wherein Z is an aryl group. In yet another embodiment is thecompound of Formula (II) shown above, having the substituents shownabove, wherein the aryl group of Z is a phenyl group. In a furtherembodiment, the phenyl group of Z is substituted with a halogen,selected from F, Br, Cl, and I. In yet another embodiment, the phenylgroup of Z is substituted with F. In yet a further embodiment the phenylgroup of Z is substituted with C₁-C₆alkylene(NR_(A)R_(B)). In yet afurther embodiment, the C₁-C₆alkylene group is methylene. In yet anotherembodiment NR_(A)R_(B) is azetidine.

In one embodiment is a compound selected from:

-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,-   (8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,    and-   (8R,9S)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,    or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one aspect is a compound selected from:

-   9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(4-(methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(hydroxymethyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(hydroxymethyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-(hydroxymethyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   5-fluoro-9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   5-fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-one;-   7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   7-ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((4-methylpiperazin-1-yl)    methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-(4-(cyclopropanecarbonyl)    piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(1,4,5-trimethyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,3-triazol-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(thiazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-ethyl-1H-imidazol-2-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((4-ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8,9-bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((3,4-dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((3,5-dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(1-methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(quinolin-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((diethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (E)-6-fluoro-4-((l-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one;-   5-fluoro-9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-((diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-(1-methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-8-(1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   9-(4-fluorophenyl)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;    and-   (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;-   or a pharmaceutical acceptable salt, solvate or prodrug therefore.

In some embodiments, provided herein is a pharmaceutical compositioncomprising of a compound of Formula (I), (IA) or (II) or stereoisomers,or a pharmaceutically acceptable salt, a pharmaceutically acceptablesolvate, pharmaceutically acceptable prodrug thereof and apharmaceutically acceptable carrier, excipient, binder or diluent.

Certain embodiments provide a method of inhibiting PARP in a subject inrecognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

In one embodiment, provided herein is a method of treating a diseaseameliorated by the inhibition of PARP comprising administering to asubject in need of treatment a therapeutically-effective amount of acompound of Formula (I), (IA) or (II). In some embodiments, the diseaseis selected from the group consisting of: vascular disease; septicshock; ischemic injury; reperfusion injury; neurotoxicity; hemorrhagicshock; inflammatory diseases; multiple sclerosis; secondary effects ofdiabetes; and acute treatment of cytotoxicity following cardiovascularsurgery.

In certain embodiments, provided herein is a method for the treatment ofcancer, comprising administering to a subject in need of treatment atherapeutically-effective amount of a compound of Formula (I), (IA) or(II).

Certain embodiments provide a method of potentiation of cytotoxic cancertherapy in a subject in recognized need of such treatment comprisingadministering to the subject a therapeutically acceptable amount of acompound of Formula (I), (IA) or (II) or a therapeutically acceptablesalt thereof.

In some embodiments, provided herein is a method for the treatment ofcancer, comprising administering to a subject in need of treatment atherapeutically-effective amount of a compound of Formula (I), (IA) or(II) in combination with ionizing radiation or one or morechemotherapeutic agents. In some embodiments, the compound describedherein is administered simultaneously with ionizing radiation or one ormore chemotherapeutic agents. In other embodiments, the compounddescribed herein is administered sequentially with ionizing radiation orone or more chemotherapeutic agents.

In certain embodiments, provided herein is a method for the treatment ofcancer, which includes administering to a subject in need of treatment atherapeutically-effective amount of a compound of Formula (I), (IA) or(II) in combination with ionizing radiation and one or morechemotherapeutic agents. In some embodiments, the compound describedherein is administered simultaneously with ionizing radiation and one ormore chemotherapeutic agents. In other embodiments, the compounddescribed herein is administered sequentially with ionizing radiationand one or more chemotherapeutic agents.

Certain embodiments provide a method of treating leukemia, colon cancer,glioblastomas, lymphomas, melanomas, carcinomas of breast, or cervicalcarcinomas in a subject in recognized need of such treatment comprisingadministering to the subject a therapeutically acceptable amount of acompound of Formula (I), (IA) or (II) or therapeutically acceptable saltthereof.

In some embodiments, provided herein is a method of treatment of acancer deficient in Homologous Recombination (HR) dependent DNA doublestrand break (DSB) repair pathway, which includes administering to asubject in need of treatment a therapeutically-effective amount of acompound of Formula (I), (IA) or (II). In certain embodiments, thecancer includes one or more cancer cells having a reduced or abrogatedability to repair DNA DSB by HR relative to normal cells. In someembodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype.In some embodiments, the cancer cells are deficient in BRCA1 or BRCA2.In some embodiments, the methods provided herein involve treatment of anindividual who is heterozygous for a mutation in a gene encoding acomponent of the HR dependent DNA DSB repair pathway. In certainembodiment, the individual is heterozygous for a mutation in BRCA1and/or BRCA2. In some embodiments, the method of treatment of a cancerincludes treatment of breast, ovary, pancreas and/or prostate cancer. Insome embodiments, the method of treatment of a cancer further includesadministration of ionizing radiation or a chemotherapeutic agent.

The primary function of the DNA mismatch repair (MMR) system is toeliminate single-base mismatches and insertion-deletion loops that mayarise during DNA replication. Insertion-deletion loops result from gainsor losses of short repeat units within microsatellite sequences, alsoknown as microsatellite instability (MSI). At least six different MMRproteins are required. For mismatch recognition, the MSH2 protein formsa heterodimer with either MSH6 or MSH3 depending on the type of lesionto be repaired (MSH6 is required for the correction of single-basemispairs, whereas both MSH3 and MSH6 may contribute to the correction ofinsertion-deletion loops). A heterodimer of MLH1 and PMS2 coordinatesthe interplay between the mismatch recognition complex and otherproteins necessary for MMR. These additional proteins may include atleast exonuclease 1 (EXO1), possibly helicase(s), proliferating cellnuclear antigen (PCNA), single-stranded DNA-binding protein (RPA), andDNA polymerases δ and ε. In addition to PMS2, MLH1 may heterodimerizewith two additional proteins, MLH3 and PMS1. Recent observationsindicate that PMS2 is required for the correction of single-basemismatches, and PMS2 and MLH3 both contribute to the correction ofinsertion-deletion loops. Additional homologs of the human MMR proteinsare known that are required for functions other than MMR. These proteinsinclude MSH4 and MSH5 that are necessary for meiotic (and possiblymitotic) recombination but are not presumed to participate in MMR.

Germline mutations of human MMR genes cause susceptibility to hereditarynonpolyposis colon cancer (HNPCC), one of the most common cancersyndromes in humans. An excess of colon cancer and a defined spectrum ofextracolonic cancers, diagnosed at an early age and transmitted as anautosomal dominant trait, constitute the clinical definition of thesyndrome. MSI, the hallmark of HNPCC, occurs in approximately 15% to 25%of sporadic tumors of the colorectum and other organs as well. Accordingto international criteria, a high degree of MSI (MSI-H) is defined asinstability at two or more of five loci or 30% to 40% of allmicrosatellite loci studied, whereas instability at fewer loci isreferred to as MSI-low (MSI-L). MSI occurs in a substantial proportion(2% to 50% of tumors) among non-HNPCC cancers (eg, cancers of thebreast, prostate, and lung). On the basis of the proportion of unstablemarkers, categories MSS, MSI-L, and MSI-H can be distinguished in thesecancers in analogy to HNPCC cancers. In one embodiment is a method fortreating a cancer deficient in mismatch DNA repair pathway. In anotherembodiment is a method for treating a cancer demonstratingmicrosatellite instability due to reduced or impaired DNA repairpathways. In another embodiment is a method for treating a cancerdemonstrating genomic instability due to reduced or impaired DNA repairpathways.

Certain embodiments provide a method of treating ischemia reperfusioninjury associated with, but not limited to, myocardial infarction,stroke, other neural trauma, and organ transplantation, in a subject inrecognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a method of treating reperfusion including,but not limited to, reperfusion of the eye, kidney, gut, and skeletalmuscle, in a subject in recognized need of such treatment comprisingadministering to the subject a therapeutically acceptable amount of acompound of Formula (I), (IA) or (II) or a therapeutically acceptablesalt thereof.

Certain embodiments provide a method of treating inflammatory diseasesincluding, but not limited to, arthritis, gout, inflammatory boweldisease, CNS inflammation, multiple sclerosis, allergic encephalitis,sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitisin a subject in recognized need of such treatment comprisingadministering to the subject a therapeutically acceptable amount of acompound of Formula (I), (IA) or (II) or a therapeutically acceptablesalt thereof.

Certain embodiments provide a method of treating immunological diseasesor disorders such a rheumatoid arthritis and septic shock in a subjectin recognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a method of treating degenerative diseasesincluding, but not limited to, diabetes and Parkinson's disease in asubject in recognized need of such treatment comprising administering tothe subject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof

Certain embodiments provide a method of treating hypoglycemia in asubject in recognized need of such treatment comprising administering tothe subject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a method of treating retroviral infection ina subject in recognized need of such treatment comprising administeringto the subject a therapeutically acceptable amount of a compound ofFormula (I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a method of treating liver toxicityfollowing acetaminophen overdose in a subject in recognized need of suchtreatment comprising administering to the subject a therapeuticallyacceptable amount of a compound of Formula (I), (IA) or (II) or atherapeutically acceptable salt thereof.

Certain embodiments provide a method of treating cardiac and kidneytoxicities from doxorubicin and platinum based antineoplastic agents ina subject in recognized need of such treatment comprising administeringto the subject a therapeutically acceptable amount of a compound ofFormula (I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a method of treating skin damage secondaryto sulfur mustards in a subject in recognized need of such treatmentcomprising administering to the subject a therapeutically acceptableamount of a compound of Formula (I), (IA) or (II) or a therapeuticallyacceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for inhibiting the PARP enzyme in a subject in recognizedneed of such treatment.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for inhibiting tumor growth in a subject in recognized needof such treatment.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating cancer in a subject in recognized need of suchtreatment.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating leukemia, colon cancer, glioblastomas, lymphomasin a subject in recognized need of such treatment.

Certain embodiments provide a method of treating degenerative diseasesincluding, but not limited to, diabetes and Parkinson's disease in asubject in recognized need of such treatment comprising administering tothe subject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for potentiation of cytotoxic cancer therapy in a subject inrecognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating ischemia reperfusion injury associated with, butnot limited to, myocardial infarction, stroke, other neural trauma, andorgan transplantation, in a subject in recognized need of such treatmentcomprising administering to the subject a therapeutically acceptableamount of a compound of Formula (I), (IA) or (II) or a therapeuticallyacceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating reperfusion including, but not limited to,reperfusion of the eye, kidney, gut and skeletal muscle, in a subject inrecognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating inflammatory diseases including, but not limitedto, arthritis, gout, inflammatory bowel disease, CNS inflammation,multiple sclerosis, allergic encephalitis, sepsis, septic shock,hemorrhagic shock, pulmonary fibrosis, and uveitis in a subject inrecognized need of such treatment comprising administering to thesubject a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating immunological diseases or disorders such asrheumatoid arthritis and septic shock in a mammal in recognized need ofsuch treatment comprising administering to the subject a therapeuticallyacceptable amount of a compound of Formula (I), (IA) or (II) or atherapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating hypoglycemia in a subject in recognized need ofsuch treatment comprising administering to the subject a therapeuticallyacceptable amount of a compound of Formula (I), (IA) or (II) or atherapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating retroviral infection in a subject in recognizedneed of such treatment comprising administering to the subject atherapeutically acceptable amount of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating liver toxicity following acetaminophen overdosein a subject in recognized need of such treatment comprisingadministering to the subject a therapeutically acceptable amount of acompound of Formula (I), (IA) or (II) or a therapeutically acceptablesalt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating cardiac and kidney toxicities from doxorubicinand platinum based antineoplastic agents in a subject in recognized needof such treatment comprising administering to the mammal atherapeutically acceptable amount of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof.

Certain embodiments provide a use of a compound of Formula (I), (IA) or(II) or a therapeutically acceptable salt thereof, to prepare amedicament for treating skin damage secondary to sulfur mustards in asubject in recognized need of such treatment comprising administering tothe mammal a therapeutically acceptable amount of a compound of Formula(I), (IA) or (II) or a therapeutically acceptable salt thereof.

Articles of manufacture, comprising packaging material, a compoundprovided herein that is effective for modulating the activity of theenzyme poly(ADP-ribose)polymerase, or for treatment, prevention oramelioration of one or more symptoms of apoly(ADP-ribose)polymerase-dependent orpoly(ADP-ribose)polymerase-mediated disease or condition, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, pharmaceuticallyacceptable N-oxide, pharmaceutically active metabolite, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, isused for modulating the activity of poly(ADP-ribose)polymerase, or fortreatment, prevention or amelioration of one or more symptoms of apoly(ADP-ribose)polymerase-dependent orpoly(ADP-ribose)polymerase-mediated disease or condition, are provided.

Any combination of the groups described above for the various variablesis contemplated herein.

In one embodiment, disclosed herein is a pharmaceutical compositioncomprising a compound, pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate of any of the compounds disclosed herein. In some embodiments,the pharmaceutical compositions further comprises a pharmaceuticallyacceptable diluent, excipient or binder. In certain embodiments, thepharmaceutical composition further comprises a second pharmaceuticallyactive ingredient.

In one embodiment, the PARP mediated disease or condition in a patient,or the PARP dependent disease or condition in a patient is cancer or anon-cancerous disorder. In some embodiments, the disease or condition isiatrogenic.

In some embodiments are methods for reducing/inhibiting the activity ofPARP in a subject that include administering to the subject at leastonce an effective amount of a compound described herein.

Certain embodiments provided herein are methods for modulating,including reducing and/or inhibiting the activity of PARP, directly orindirectly, in a subject comprising administering to the subject atleast once an effective amount of at least one compound describedherein.

In further embodiments are methods for treating PARP mediated conditionsor diseases, comprising administering to the subject at least once aneffective amount of at least one compound described herein.

Some embodiments include the use of a compound described herein in themanufacture of a medicament for treating a disease or condition in asubject in which the activity of at least one PARP protein contributesto the pathology and/or symptoms of the disease or condition.

In any of the aforementioned embodiments are further embodiments inwhich administration is enteral, parenteral, or both, and wherein:

-   -   (a) the effective amount of the compound is systemically        administered to the subject;    -   (b) the effective amount of the compound is administered orally        to the subject;    -   (c) the effective amount of the compound is intravenously        administered to the subject;    -   (d) the effective amount of the compound administered by        inhalation;    -   (e) the effective amount of the compound is administered by        nasal administration;    -   (f) the effective amount of the compound is administered by        injection to the subject;    -   (g) the effective amount of the compound is administered        topically (dermal) to the subject;    -   (h) the effective amount of the compound is administered by        ophthalmic administration; and/or    -   (i) the effective amount of the compound is administered        rectally to the subject.

In any of the aforementioned embodiments are further embodiments thatinclude single administrations of the effective amount of the compound,including further embodiments in which the compound is administered tothe subject (i) once; (ii) multiple times over the span of one day;(iii) continually; or (iv) continuously.

In any of the aforementioned embodiments are further embodiments thatinclude multiple administrations of the effective amount of thecompound, including further embodiments wherein:

-   -   (i) the compound is administered in a single dose;    -   (ii) the time between multiple administrations is every 6 hours;    -   (iii) the compound is administered to the subject every 8 hours.

In further or alternative embodiments, the method includes a drugholiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. In some embodiments, the length of the drug holiday varies from2 days to 1 year.

In any of the aforementioned embodiments involving the treatment ofproliferative disorders, including cancer, are further embodiments thatinclude administering at least one additional agent selected from amongalemtuzumab, arsenic trioxide, asparaginase (pegylated or non-),bevacizumab, cetuximab, platinum-based compounds such as cisplatin,cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, paclitaxel,Taxol®, temozolomide, thioguanine, and classes of drugs includinghormones (an antiestrogen, an antiandrogen, or gonadotropin releasinghormone analogues, interferons such as, for example, alpha interferon,nitrogen mustards such as, for example, busulfan, melphalan ormechlorethamine, retinoids such as, for example, tretinoin,topoisomerase inhibitors such as, for example, irinotecan or topotecan,tyrosine kinase inhibitors such as, for example, gefinitinib orimatinib, and agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,and dronabinol.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdescription. It should be understood, however, that the description andthe specific examples, while indicating specific embodiments, are givenby way of illustration only, since various changes and modificationswithin the spirit and scope of the present description will becomeapparent from this detailed description.

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments that include such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with PARP activity.

Described herein are compounds having activity in inhibiting the enzymepoly(ADP-ribose)polymerase (PARP). In some embodiments, the compoundshave the structure set forth in Formula (I), (IA) or (II).

The mammalian enzyme PARP-1 is a multidomain protein. PARP-1 isimplicated in the signaling of DNA damage through its ability torecognize and rapidly bind to DNA single or double strand breaks.D'Amours, et al., Biochem. J., 342, 249-268 (1999); and Virag et al.Pharmacological Reviews, vol. 54, no. 3, 375-429 (2002) are herebyincorporated by reference for such disclosure.

The family of poly(ADP-ribose)polymerases includes approximately 18proteins, which all display a certain level of homology in theircatalytic domain but differ in their cellular functions. PARP-1 andPARP-2 are unique members of the family, in that their catalyticactivities are stimulated by the occurrence of DNA strand breaks. Ame etal., BioEssays., 26(8), 882-893 (2004) is hereby incorporated byreference for such disclosure.

PARP-1 participates in a variety of DNA-related functions including geneamplification, cell division, differentiation, apoptosis, DNA baseexcision repair as well as effects on telomere length and chromosomestability. d'Adda di Fagagna, et al., Nature Gen., 23(1), 76-80 (1999)is hereby incorporated by reference for such disclosure.

Studies on the mechanism by which PARP-1 modulates DNA repair and otherprocesses identifies its importance in the formation of poly(ADP-ribose)chains within the cellular nucleus. The DNA-bound, activated PARP-1utilizes NAD+ to synthesize poly(ADP-ribose) on a variety of nucleartarget proteins, including topoisomerases, histones and PARP itself.Althaus, F. R. and Richter, C., ADP-Ribosylation of Proteins: Enzymologyand Biological Significance, Springer-Verlag, Berlin (1987); and Rhun,et al., Biochem. Biophys. Res. Commun., 245, 1-10 (1998) are herebyincorporated by reference for such disclosure.

Poly(ADP-ribosyl)ation is also associated with malignant transformation.For example, PARP-1 activity is higher in the isolated nuclei ofSV40-transformed fibroblasts, while both leukemic cells and colon cancercells show higher enzyme activity than the equivalent normal leukocytesand colon mucosa. Furthermore, malignant prostate tumors have increasedlevels of active PARP as compared to benign prostate cells, which isassociated with higher levels of genetic instability. Miwa, et al.,Arch. Biochem. Biophys., 181, 313-321 (1977); Burzio, et al., Proc. Soc.Exp. Biol. Med., 149, 933-938 (1975); Hirai, et al., Cancer Res., 43,3441-3446 (1983); and Mcnealy, et al., Anticancer Res., 23, 1473-1478(2003) are hereby incorporated by reference for such disclosure.

In cells treated with alkylating agents, the inhibition of PARP leads toa marked increase in DNA-strand breakage and cell killing. PARP-1inhibitors also enhance the effects of radiation response by suppressingthe repair of potentially lethal damage. PARP inhibitors are alsoeffective in radio-sensitizing hypoxic tumor cells. In certain tumorcell lines, chemical inhibition of PARP activity is also associated withmarked sensitization to very low doses of radiation.

Furthermore, PARP-1 knockout (PARP−/−) animals exhibit genomicinstability in response to alkylating agents and γ-irradiation. Dataindicates that PARP-1 and PARP-2 possess both overlapping andnon-redundant functions in the maintenance of genomic stability, makingthem both interesting targets. Wang, et al., Genes Dev., 9, 509-520(1995); Menissier de Murcia, et al., Proc. Natl. Acad. Sci. USA, 94,7303-7307 (1997); and Menissier de Murcia, et al., EMBO. J., 22(9),2255-2263 (2003) are hereby incorporated by reference for suchdisclosure.

There is also a role for PARP-1 in certain vascular diseases, such as,for example, septic shock, ischaemic injury and neurotoxicity. Oxygenradical DNA damage that leads to strand breaks in DNA, which aresubsequently recognized by PARP-1, is a major contributing factor tosuch disease states as shown by PARP-1 inhibitor studies. PARP alsoplays a role in the pathogenesis of hemorrhagic shock. Cantoni, et al.,Biochim. Biophys. Acta, 1014, 1-7 (1989); Szabo, et al., J. Clin.Invest., 100, 723-735 (1997); Cosi, et al., J. Neurosci. Res., 39, 3846(1994); Said, et al., Proc. Natl. Acad. Sci. USA., 93, 4688-4692 (1996);and Liaudet, et al., Proc. Natl. Acad. Sci. USA., 97(3), 10203-10208(2000) are hereby incorporated by reference for such disclosure.

Furthermore, efficient retroviral infection of mammalian cells isblocked by the inhibition of PARP-1 activity. Such inhibition ofrecombinant retroviral vector infections occurs in various differentcell types. In some embodiments, inhibitors of PARP-1 are used inanti-viral therapies and in cancer treatment. Gaken, et al., J.Virology, 70(6), 3992-4000 (1996) is hereby incorporated by referencefor such disclosure.

Moreover, in certain embodiments, PARP-1 inhibition delays the onset ofaging characteristics in human fibroblasts. While not intending to boundby any theory, this may be related to the role that PARP plays incontrolling telomere function. Rattan and Clark, Biochem. Biophys. Res.Comm., 201(2), 665-672 (1994); and d'Adda di Fagagna, et al., NatureGen., 23(1), 76-80 (1999) are hereby incorporated by reference for suchdisclosure.

In some embodiments, PARP inhibitors are relevant to the treatment ofinflammatory bowel disease, ulcerative colitis and Crohn's disease.Szabo C., Role of Poly(ADP-Ribose) Polymerase Activation in thePathogenesis of Shock and Inflammation, In PARP as a Therapeutic Target;Ed J. Zhang, 2002 by CRC Press; 169-204; Zingarelli, B, et al.,Immunology, 113(4), 509-517 (2004); and Jijon, H. B., et al., Am. J.Physiol. Gastrointest. Liver Physiol., 279, G641-G651 (2000) are herebyincorporated by reference for such disclosure.

In certain embodiments, PARP inhibitors, such as those of Formula (I),(IA) or (II), have utility in: (a) preventing or inhibitingpoly(ADP-ribose) chain formation by, e.g., inhibiting the activity ofcellular PARP (PARP-1 and/or PARP-2); (b) treating vascular disease;septic shock; ischaemic injury, both cerebral and cardiovascular;reperfusion injury, both cerebral and cardiovascular; neurotoxicity,including acute and chronic treatments for stroke and Parkinson'sdisease; hemorrhagic shock; inflammatory diseases, such as arthritis,inflammatory bowel disease, ulcerative colitis and Crohn's disease;multiple sclerosis; secondary effects of diabetes; as well as the acutetreatment of cytotoxicity following cardiovascular surgery or diseasesameliorated by the inhibition of the activity of PARP; (c) use as anadjunct in cancer therapy or for potentiating tumor cells for treatmentwith ionizing radiation and/or chemotherapeutic agents.

In specific embodiments, compounds provided herein, such as, forexample, Formula (I), (IA) or (II), are used in anti-cancer combinationtherapies (or as adjuncts) along with alkylating agents, such as methylmethanesulfonate (MMS), temozolomide and dacarbazine (DTIC), also withtopoisomerase-1 inhibitors like Topotecan, Irinotecan, Rubitecan,Exatecan, Lurtotecan, Gimetecan, Diflomotecan (homocamptothecins); aswell as 7-substituted non-silatecans; the 7-silyl camptothecins, BNP1350; and non-camptothecin topoisomerase-I inhibitors such asindolocarbazoles also dual topoisomerase-I and II inhibitors like thebenzophenazines, XR 11576/MLN 576 and benzopyridoindoles. In certainembodiments, such combinations are given, for example, as intravenouspreparations or by oral administration as dependent on the method ofadministration for the particular agent.

In some embodiments, PARP inhibitors, such as, for example, compounds ofFormula (I), (IA) or (II), are used in the treatment of diseaseameliorated by the inhibition of PARP, which includes administering to asubject in need of treatment a therapeutically-effective amount of acompound provided herein, and in one embodiment in the form of apharmaceutical composition. In certain embodiments, PARP inhibitors,such as, for example, compounds of Formula (I), (IA) or (II), are usedin the treatment of cancer, which includes administering to a subject inneed of treatment a therapeutically-effective amount of a compoundprovided herein in combination, and in one embodiment in the form of apharmaceutical composition, simultaneously or sequentially withradiotherapy (ionizing radiation) or chemotherapeutic agents.

In certain embodiments, PARP inhibitors, such as, for example, compoundsof Formula (I), (IA) or (II), are used in the preparation of amedicament for the treatment of cancer which is deficient in HomologousRecombination (HR) dependent DNA double strand break (DSB) repairactivity, or in the treatment of a patient with a cancer which isdeficient in HR dependent DNA DSB repair activity, which includesadministering to said patient a therapeutically-effective amount of thecompound.

The HR dependent DNA DSB repair pathway repairs double-strand breaks(DSBs) in DNA via homologous mechanisms to reform a continuous DNAhelix. The components of the HR dependent DNA DSB repair pathwayinclude, but are not limited to, ATM (NM_000051), RAD51 (NM_002875),RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1(NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879),RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2(NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485).Other proteins involved in the HR dependent DNA DSB repair pathwayinclude regulatory factors such as EMSY. HR components are alsodescribed in Wood, et al., Science, 291, 1284-1289 (2001), which ishereby incorporated by reference for such disclosure. K. K. Khanna andS. P. Jackson, Nat. Genet. 27(3): 247-254 (2001); and Hughes-Davies, etal., Cell, 115, pp 523-535 are also incorporated herein by reference forsuch disclosure.

In some embodiments, a cancer which is deficient in HR dependent DNA DSBrepair includes one or more cancer cells which have a reduced orabrogated ability to repair DNA DSBs through that pathway, relative tonormal cells, i.e. the activity of the HR dependent DNA DSB repairpathway are reduced or abolished in the one or more cancer cells.

In certain embodiments, the activity of one or more components of the HRdependent DNA DSB repair pathway is abolished in the one or more cancercells of an individual having a cancer which is deficient in HRdependent DNA DSB repair. Components of the HR dependent DNA DSB repairpathway include the components listed above.

In some embodiments, the cancer cells have a BRCA1 and/or a BRCA2deficient phenotype, i.e., BRCA1 and/or BRCA2 activity is reduced orabolished in the cancer cells. In certain embodiments, cancer cells withthis phenotype are deficient in BRCA1 and/or BRCA2, i.e., expressionand/or activity of BRCA1 and/or BRCA2 is reduced or abolished in thecancer cells, for example by means of mutation or polymorphism in theencoding nucleic acid, or by means of amplification, mutation orpolymorphism in a gene encoding a regulatory factor, for example theEMSY gene which encodes a BRCA2 regulatory factor or by an epigeneticmechanism such as gene promoter methylation.

BRCA1 and BRCA2 are tumor suppressors whose wild-type alleles arefrequently lost in tumors of heterozygous carriers. BRCA1 and/or BRCA2mutations are associated with breast cancer. Amplification of the EMSYgene, which encodes a BRCA2 binding factor, is associated with breastand ovarian cancer. Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, etal., Trends Mol Med., 8(12), 571-6, (2002); and Radice, P. J., Exp ClinCancer Res., 21(3 Suppl), 9-12 (2002) are hereby incorporated byreference for such disclosure.

Carriers of mutations in BRCA1 and/or BRCA2 are also at elevated risk ofcancer of the ovary, prostate and pancreas.

In some embodiments, the individual is heterozygous for one or morevariations, such as mutations and polymorphisms, in BRCA1 and/or BRCA2or a regulator thereof. The detection of variation in BRCA1 and BRCA2 isdescribed, for example in EP 699 754, EP 705 903, Neuhausen, S. L. andOstrander, E. A., Genet. Test, 1, 75-83 (1992); Janatova M., et al.,Neoplasma, 50(4), 246-50 (2003), which is hereby incorporated byreference for such disclosure. Determination of amplification of theBRCA2 binding factor EMSY is described in Hughes-Davies, et al., Cell,115, 523-535).

In certain instances, mutations and polymorphisms associated with cancerare detected at the nucleic acid level by detecting the presence of avariant nucleic acid sequence or at the protein level by detecting thepresence of a variant (i.e. a mutant or allelic variant) polypeptide.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the standard meaning pertaining to the claimed subject matterbelongs. In the event that there are a plurality of definitions forterms herein, those in this section prevail. Where reference is made toa URL or other such identifier or address, it understood that suchidentifiers can change and particular information on the internet cancome and go, but equivalent information can be found by searching theinternet. Reference thereto evidences the availability and publicdissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed. Unless specific definitions are provided,the standard nomenclature employed in connection with, and the standardlaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry areemployed. In certain instances, standard techniques are used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. In certainembodiments, standard techniques are used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). In some embodiments, reactions andpurification techniques are performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished or as described herein.

As used throughout this application and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight, branched chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”)hydrocarbon containing from 2-10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens. Insome embodiments, depending on the structure, an alkenyl group is amonoradical or a diradical (i.e., an alkenylene group). In someembodiments, alkenyl groups are optionally substituted. Illustrativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, and 3-cecenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Illustrative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight, branched chain, orcyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-10 carbon atoms. Illustrative examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “C₁-C₆-alkyl” as used herein, means a straight, branched chain,or cyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-6 carbon atoms. Representative examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, cyclopyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl,n-pentyl, isopentyl, neopentyl, cyclopentyl, and n-hexyl.

The term “cycloalkyl” as used herein, means a monocyclic or polycyclicradical that contains only carbon and hydrogen, and includes those thatare saturated, partially unsaturated, or fully unsaturated. Cycloalkylgroups include groups having from 3 to 10 ring atoms. Representativeexamples of cyclic include but are not limited to, the followingmoieties:

In some embodiments, depending on the structure, a cycloalkyl group is amonoradical or a diradical (e.g., a cycloalkylene group).

The term “cycloalkyl groups” as used herein refers to groups which areoptionally substituted with 1, 2, 3, or 4 substituents selected fromalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene,mercapto, oxo, —NR_(A)R_(A), and (NR_(A)R_(B))carbonyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, 5-cycloheptylbutyl.

The term “carbocyclic” as used herein, refers to a compound whichcontains one or more covalently closed ring structures, and that theatoms forming the backbone of the ring are all carbon atoms

The term “carbocycle” as used herein, refers to a ring, wherein each ofthe atoms forming the ring is a carbon atom. Carbocylic rings includethose formed by three, four, five, six, seven, eight, nine, or more thannine carbon atoms. Carbocycles are optionally substituted.

The term “alkoxyalkyl” as used herein, means at least one alkoxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Illustrative examples of alkoxyalkylinclude, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl,tert-butoxyethyl and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Illustrative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Illustrative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Illustrative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylthio” or “thioalkoxy” as used herein, means an alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom. Illustrative examples of alkylthio include, butare not limited to, methylthio, ethylthio, butylthio, tert-butylthio,and hexylthio.

The term “alkylthioalkyl” as used herein, means an alkylthio group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Illustrative examples of alkylthioalkylinclude, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl,butylthiomethyl, and hexylthioethyl.

The term “alkynyl” as used herein, means a straight, branched chainhydrocarbon containing from 2-10 carbons and containing at least onecarbon-carbon triple bond. In some embodiments, alkynyl groups areoptionally substituted. Illustrative examples of alkynyl include, butare not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “aromatic” as used herein, refers to a planar ring having adelocalized it-electron system containing 4n+2 π electrons, where n isan integer. In some embodiments, aromatic rings are formed by five, six,seven, eight, nine, or more than nine atoms. In other embodiments,aromatics are optionally substituted. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of carbonatoms) groups.

The term “aryl” as used herein, refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In some embodiments,aryl rings are formed by five, six, seven, eight, nine, or more thannine carbon atoms. Examples of aryl groups include, but are not limitedto phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, andindenyl.

In some embodiments, the term “aryl” as used herein means an aryl groupthat is optionally substituted with one, two, three, four or fivesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carbonyl, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene,mercapto, nitro, —NR_(A)R_(A), and (NR_(A)R_(B))carbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Illustrative examples of arylalkyl include, but arenot limited to benzyl, 2-phenylethyl, -phenylpropyl,1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —COOH group.

The term “cyano” as used herein, means a —CN group.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means a —Cl, —Br, —I or —F.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “hydroxy” as used herein, means a —OH group.

The term “oxo” as used herein, means a ═O group.

The term “bond” or “single bond” as used herein, refers to a chemicalbond between two atoms, or two moieties when the atoms joined by thebond are considered to be part of larger substructure.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” asused herein, include alkyl, alkenyl, alkynyl and alkoxy structures inwhich at least one hydrogen is replaced with a halogen atom. In certainembodiments in which two or more hydrogen atoms are replaced withhalogen atoms, the halogen atoms are all the same as one another. Inother embodiments in which two or more hydrogen atoms are replaced withhalogen atoms, the halogen atoms are not all the same as one another.The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl andhaloalkoxy groups, respectively, in which the halo is fluorine. Incertain embodiments, haloalkyls are optionally substituted.

The term “alkylamine” refers to the N(alkyl)_(x)H_(y) group, where x andy are selected from among x=1, y=1 and x=2, y=0. In some embodiments,when x=2, the alkyl groups, taken together with the N atom to which theyare attached, optionally form a cyclic ring system.

The term “amide” as used herein, is a chemical moiety with the formula—C(O)NHR or —NHC(O)R, where R is selected from among hydrogen, alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheterocycloalkyl (bonded through a ring carbon). In some embodiments, anamide moiety forms a linkage between an amino acid or a peptide moleculeand a compound described herein, thereby forming a prodrug. In someembodiments, any amine, or carboxyl side chain on the compoundsdescribed herein is amidified.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heterocycloalkyl (bonded through a ringcarbon). In some embodiments, any hydroxy, or carboxyl side chain on thecompounds described herein is esterified.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” as usedherein, include optionally substituted alkyl, alkenyl and alkynylradicals in which one or more skeletal chain atoms are selected from anatom other than carbon, e.g., oxygen, nitrogen, sulfur, silicon,phosphorus or combinations thereof.

The term “heteroatom” as used herein refers to an atom other than carbonor hydrogen. Heteroatoms are typically independently selected from amongoxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited tothese atoms. In embodiments in which two or more heteroatoms arepresent, the two or more heteroatoms are all the same as one another, orsome or all of the two or more heteroatoms are each different from theothers.

The term “ring” as used herein, refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and heterocycloalkyls),aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g.,cycloalkyls and heterocycloalkyls). In some embodiments, rings areoptionally substituted. In some embodiments, rings form part of a ringsystem.

As used herein, the term “ring system” refers to two or more rings,wherein two or more of the rings are fused. The term “fused” refers tostructures in which two or more rings share one or more bonds.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. In some embodiments,the polycyclic heteroaryl group is fused or non-fused. Illustrative ofheteroaryl groups include, but are not limited to, the followingmoieties:

In some embodiments, depending on the structure, a heteroaryl group is amonoradical or a diradical (i.e., a heteroarylene group).

The term “heteroaryl” means heteroaryl groups that are substituted with0, 1, 2, 3, or 4 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene,mercapto, nitro, —NR_(A)R_(B), and (NR_(A)R_(B))carbonyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Illustrative examples of heteroarylalkylinclude, but are not limited to, pyridinylmethyl.

The term “heterocycloalkyl” or “non-aromatic heterocycle” as usedherein, refers to a non-aromatic ring wherein one or more atoms formingthe ring is a heteroatom. A “heterocycloalkyl” or “non-aromaticheterocycle” group refers to a cycloalkyl group that includes at leastone heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, the radicals are fused with an aryl or heteroaryl. In someembodiments, heterocycloalkyl rings are formed by three, four, five,six, seven, eight, nine, or more than nine atoms. In some embodiments,heterocycloalkyl rings are optionally substituted. In certainembodiments, heterocycloalkyls contain one or more carbonyl orthiocarbonyl groups such as, for example, oxo- and thio-containinggroups. Examples of heterocycloalkyls include, but are not limited to,lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include, but are not limitedto

The term heterocycloalkyl also includes all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “heterocycle” refers to heteroaryl and heterocycloalkyl usedherein, refers to groups containing one to four heteroatoms eachselected from O, S and N, wherein each heterocycle group has from 4 to10 atoms in its ring system, and with the proviso that the ring of saidgroup does not contain two adjacent O or S atoms. Herein, whenever thenumber of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one other atom (the heteroatom) must be presentin the ring. Designations such as “C₁-C₆ heterocycle” refer only to thenumber of carbon atoms in the ring and do not refer to the total numberof atoms in the ring. In some embodiments, it is understood that theheterocycle ring has additional heteroatoms in the ring. Designationssuch as “4-6 membered heterocycle” refer to the total number of atomsthat are contained in the ring (i.e., a four, five, or six memberedring, in which at least one atom is a carbon atom, at least one atom isa heteroatom and the remaining two to four atoms are either carbon atomsor heteroatoms). In some embodiments, in heterocycles that have two ormore heteroatoms, those two or more heteroatoms are the same ordifferent from one another. In some embodiments, heterocycles areoptionally substituted. In some embodiments, binding to a heterocycle isat a heteroatom or via a carbon atom. Heterocycloalkyl groups includegroups having only 4 atoms in their ring system, but heteroaryl groupsmust have at least 5 atoms in their ring system. The heterocycle groupsinclude benzo-fused ring systems. An example of a 4-membered heterocyclegroup is azetidinyl (derived from azetidine). An example of a 5-memberedheterocycle group is thiazolyl. An example of a 6-membered heterocyclegroup is pyridyl, and an example of a 10-membered heterocycle group isquinolinyl. Examples of heterocycloalkyl groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of heteroaryl groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. In some embodiments, the foregoing groups, as derivedfrom the groups listed above, are C-attached or N-attached where such ispossible. For instance, in some embodiments, a group derived frompyrrole is pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, in some embodiments, a group derived from imidazole isimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocycle groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one. In some embodiments,depending on the structure, a heterocycle group is a monoradical or adiradical (i.e., a heterocyclene group).

The heterocycles described herein are substituted with 0, 1, 2, 3, or 4substituents independently selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, —NR_(A)R_(B), and(NR_(A)R_(B))carbonyl.

The term “heterocycloalkoxy” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkoxy group.

The term “heterocycloalkylthio” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkylthio group.

The term “heterocyclooxy” refers to a heterocycloalkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heterocyclothio” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom.

The term “heteroarylalkoxy” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group.

The term “heteroarylalkylthio” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an alkylthiogroup.

The term “heteroaryloxy” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroarylthio” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.

In some embodiments, the term “membered ring” embraces any cyclicstructure. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, for example, cyclohexyl, pyridine,pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,furan, and thiophene are 5-membered rings.

The term “non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12-bicyclic heterocycle”as used herein, means a heterocycloalkyl, as defined herein, consistingof two carbocyclic rings, fused together at the same carbon atom(forming a spiro structure) or different carbon atoms (in which tworings share one or more bonds), having 5 to 12 atoms in its overall ringsystem, wherein one or more atoms forming the ring is a heteroatom.Illustrative examples of non-aromatic 5, 6, 7, 8, 9, 10, 11, or12-bicyclic heterocycle ring include, but are not limited to,2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl,2-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.2.0]heptanyl,4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-azaspiro[2.5]octanyl,5-azaspiro[2.5]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl,4-oxa-7-azaspiro[2.5]octanyl, 2-azabicyclo[2.2.2]octanyl,1,3-diazabicyclo[2.2.2]octanyl, 5-azaspiro[3.5]nonanyl,6-azaspiro[3.5]nonanyl, 5-oxo-8-azaspiro[3.5]nonanyl,octahydrocyclopenta[c]pyrrolyl, octahydro-1H-quinolizinyl,2,3,4,6,7,9a-hexahydro-1H-quinolizinyl, decahydropyrido[1,2-a]azepinyl,decahydro-1H-pyrido[1,2-a]azocinyl, 1-azabicyclo[2.2.1]heptanyl,1-azabicyclo[3.3.1]nonanyl, quinuclidinyl, and1-azabicyclo[4.4.0]decanyl.

The term hydroxyalkylene” as used herein, means at least one hydroxylgroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Illustrative examples ofhydroxyalkylene include, but not limited to hydroxymethylene,2-hydroxy-ethylene, 3-hydroxypropylene and 4-hydroxyheptylene.

The term “NR_(A)NR_(B)” as used herein, means two group, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,and alkylcarbonyl. Illustrative examples of NR_(A)R_(B) include, but arenot limited to, amino, methylamino, acetylamino, and acetylmethylamino.

The term “(NR_(A)NR_(B))carbonyl” as used herein, means a R_(A)R_(B),group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Illustrative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(C)NR_(D)” as used herein, means two group, R_(C) andR_(D), which are appended to the parent molecular moiety through anitrogen atom. R_(C) and R_(D) are each independently hydrogen, alkyl,and alkylcarbonyl. Illustrative examples of NR_(C)R_(D) include, but arenot limited to, amino, methylamino, acetylamino, and acetylmethylamino.

The term “(NR_(C)NR_(D))carbonyl” as used herein, means a R_(C)R_(D),group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Illustrative examples of(NR_(C)R_(D))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

As used herein, the term “mercaptyl” refers to a (alkyl)S— group.

As used herein, the term “moiety” refers to a specific segment orfunctional group of a molecule. Chemical moieties are often recognizedchemical entities embedded in or appended to a molecule.

As used herein, the term “sulfinyl” refers to a —S(═O)—R, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon).

As used herein, the term “sulfonyl” refers to a —S(═O)₂—R, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon).

As used herein, the term “O carboxy” refers to a group of formulaRC(═O)O—.

As used herein, the term “C carboxy” refers to a group of formula—C(═O)OR.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

As used herein, the term “isocyanato” refers to a group of formula —NCO.

As used herein, the term “thiocyanato” refers to a group of formula—CNS.

As used herein, the term “isothiocyanato” refers to a group of formula—NCS.

As used herein, the term “S sulfonamido” refers to a group of formula—S(═O)₂NR₂.

As used herein, the term “N sulfonamido” refers to a group of formulaRS(═O)₂NH—.

As used herein, the term “trihalomethanesulfonamido” refers to a groupof formula X₃CS(═O)₂NR—.

As used herein, the term “O carbamyl” refers to a group of formula—OC(═O)NR₂.

As used herein, the term “N carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O thiocarbamyl” refers to a group of formula—OC(═S)NR₂.

As used herein, the term “N thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C amido” refers to a group of formula—C(═O)NR₂.

As used herein, the term “N amido” refers to a group of formulaRC(═O)NH—.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

The term “substituted” means that the referenced group is optionallysubstituted (substituted or unsubstituted) with one or more additionalgroup(s) individually and independently selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone,arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl,and amino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. By way of example an optionalsubstituents is L_(s)R_(s), wherein each L_(s) is independently selectedfrom a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—,—C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, -(substituted orunsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted C₂-C₆alkenyl); and each R_(s) is independently selected from H, (substitutedor unsubstituted lower alkyl), (substituted or unsubstituted lowercycloalkyl), heteroaryl, or heteroalkyl.

The term “protecting group” refers to a removable group which modifiesthe reactivity of a functional group, for example, a hydroxyl, ketone oramine, against undesirable reaction during synthetic procedures and tobe later removed. Examples of hydroxy-protecting groups include, but notlimited to, methylthiomethyl, tert-dimethylsilyl,tert-butyldiphenylsilyl, ethers such as methoxymethyl, and estersincluding acetyl, benzoyl, and the like. Examples of ketone protectinggroups include, but not limited to, ketals, oximes, O-substituted oximesfor example O-benzyl oxime, O-phenylthiomethyl oxime,1-isopropoxycyclohexyl oxime, and the like. Examples of amine protectinggroups include, but are not limited to, tert-butoxycarbonyl (Boc) andcarbobenzyloxy (Cbz).

The term “optionally substituted” as defined herein, means thereferenced group is substituted with zero, one or more substituents asdefined herein.

The term “protected-hydroxy” refers to a hydroxy group protected with ahydroxy protecting group, as defined above.

In some embodiments, compounds of the described herein exist asstereoisomers, wherein asymmetric or chiral centers are present.Stereoisomers are designated (R) or (S) depending on the configurationof substituents around the chiral carbon atom. The term (R) and (S) usedherein are configurations as defined in IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl. Chem., (1976),45:13-30, hereby incorporated by reference. The embodiments describedherein specifically includes the various stereoisomers and mixturesthereof. Stereoisomers include enantiomers, diastereomers, and mixturesof enantiomers or diastereomers. In some embodiments, individualstereoisomers of compounds are prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral axillary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic column.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In some embodiments, the compounds described herein exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Throughout the specification, groups and substituents thereof arechosen, in certain embodiments, to provide stable moieties andcompounds.

Preparation of Compounds Described Herein

In certain embodiments, the compounds described herein are synthesizedusing any synthetic techniques including standard synthetic techniquesand the synthetic processes described herein. In specific embodiments,the following synthetic processes are utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

Selected examples of covalent linkages and precursor functional groupswhich yield them are given in the Table entitled “Examples of CovalentLinkages and Precursors Thereof.” Precursor functional groups are shownas electrophilic groups and nucleophilic groups. In certain embodiments,a functional group on an organic substance is attached directly, orattached via any useful spacer or linker as defined below.

TABLE 1 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

In general, carbon electrophiles are susceptible to attack bycomplementary nucleophiles, including carbon nucleophiles, wherein anattacking nucleophile brings an electron pair to the carbon electrophilein order to form a new bond between the nucleophile and the carbonelectrophile.

Suitable carbon nucleophiles include, but are not limited to alkyl,alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-,alkenyl, aryl- and alkynyl-tin reagents (organostannanes), alkyl-,alkenyl-, aryl- and alkynyl-borane reagents (organoboranes andorganoboronates); these carbon nucleophiles have the advantage of beingkinetically stable in water or polar organic solvents. Other carbonnucleophiles include phosphorus ylids, enol and enolate reagents; thesecarbon nucleophiles have the advantage of being relatively easy togenerate from precursors. Carbon nucleophiles, when used in conjunctionwith carbon electrophiles, engender new carbon-carbon bonds between thecarbon nucleophile and carbon electrophile.

Non-carbon nucleophiles suitable for coupling to carbon electrophilesinclude but are not limited to primary and secondary amines, thiols,thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides,and the like. These non-carbon nucleophiles, when used in conjunctionwith carbon electrophiles, typically generate heteroatom linkages(C—X—C), wherein X is a heteroatom, e. g, oxygen or nitrogen.

Use of Protecting Groups

The term “protecting group” refers to chemical moieties that block someor all reactive moieties and prevent such groups from participating inchemical reactions until the protective group is removed. In specificembodiments, more than one protecting group is utilized. In morespecific embodiments, each protective group is removable by a differentprocess. Protective groups that are cleaved under totally disparatereaction conditions fulfill the requirement of differential removal. Invarious embodiments, protective groups are removed by acid, base, orhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are, in some embodiments, usedto protect carboxy and hydroxy reactive moieties in the presence ofamino groups protected with Cbz groups, which are removable byhydrogenolysis, and Fmoc groups, which are base labile. In someembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith base labile groups such as, without limitation, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

In certain embodiments, carboxylic acid and hydroxy reactive moietiesare blocked with hydrolytically removable protective groups such as thebenzyl group, while, in some embodiments, amine groups capable ofhydrogen bonding with acids are blocked with base labile groups such asFmoc. In various embodiments, carboxylic acid reactive moieties areprotected by conversion to simple ester derivatives as exemplifiedherein, or they are blocked with oxidatively-removable protective groupssuch as 2,4-dimethoxybenzyl, while, in some embodiments, co-existingamino groups are blocked with fluoride labile silyl carbamates.

In certain instances, allyl blocking groups are useful in the presenceof acid- and base-protecting groups since the former are stable. In someembodiments, such groups are subsequently removed by metal or pi-acidcatalysts. For example, in some embodiments, an allyl-blocked carboxylicacid is deprotected with a Pd⁰-catalyzed reaction in the presence ofacid labile t-butyl carbamate or base-labile acetate amine protectinggroups. In some embodiments, a protecting group is a resin to which acompound or intermediate is attached. As long as the residue is attachedto the resin, that functional group is blocked and cannot react. Oncereleased from the resin, the functional group is available to react.

In some embodiments, blocking/protecting groups are selected from, byway of non-limiting example:

Other protecting groups are described in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y.,1999.

Compounds of Formula (I)

In certain embodiments, compounds of Formula (I), composing of Ia to If,are prepared in various ways, as outlined in Synthetic Schemes 1 and 2.In each scheme, the variables (e.g., R₁, R₂, R₃, R₄, R₅, Y, and Z)correspond to the same definitions as those recited above while R isalkyl and Y′ is the same or different group defined by Y and Z′ is thesame or different group defined by Z. In some embodiments, compounds aresynthesized using methodologies analogous to those described below bythe use of appropriate alternative starting materials.

In certain embodiments, compounds of Formula (Ia, and Ib) wherein Y isidentical to Z are synthesized according to Synthetic Scheme 1. Thus,the preparation of the intermediate 3 wherein R₅ is hydrogen is achievedby condensation of 4-aminoisobenzofuran-1(3H)-one 1 with an aldehyde 2in the presence of a base preferably alkaline alkoxides in appropriatesolvents such as ethyl acetate or ethyl propionate at either ambient orelevated temperature. Compounds of Formula Ia wherein R₅ is hydrogen isprepared by treating the intermediate 3 with hydrazine hydrate atambient or elevated temperature. Compounds of Formula Ia wherein R₅ isalkyl or substituted alkyl is prepared from compound of Formula Iawherein R₅ is hydrogen by reductive amination reaction with R₇—CHOwherein R₇ is alkyl, substituted alkyl. In some embodiments, thepreparation of the compounds in Formula Ib is accomplished by furthermodification of Ia. Through appropriate functional group transformationson the moiety of Y and Z, one affords the compounds of Formula Ib withdifferent entities of Y′ and Z′ at 2- or 3-positions.

In certain embodiments, compounds of Formula (Ic, and Id) aresynthesized according to Synthetic Scheme 2. For example, theintermediate 5 is prepared by condensation of the reagent 1 with analdehyde 4 in the presence of water absorbent such sodium sulfate ormagnesium sulfate at elevated temperature. A subsequent condensationreaction of this intermediate with another aldehyde in the presence of abase preferably alkaline alkoxides in appropriate solvents such as ethylacetate or ethyl propionate at either ambient or elevated temperaturegives the intermediate 6 wherein R₅ is hydrogen. Compounds of Formula Icwherein R₅ is hydrogen is prepared by treating the intermediate 6 withhydrazine hydrate at ambient or elevated temperature. Compounds ofFormula Ic wherein R₅ is alkyl, substituted alkyl are prepared fromcompounds of Formula Ic wherein R₅ is hydrogen by reductive aminationreaction with R₇—CHO wherein R₇ is alkyl, or substituted alkyl. In someembodiments, the preparation of compounds of Formula Id are accomplishedby further modification of Ic. Through appropriate functional grouptransformations on the moiety of Y and Z, one could afford the compoundsof Formula Ic with different entities of Y′ and Z′ at 2- or 3-positions.

Certain Pharmaceutical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, PARP, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least about 10, about 50, about 100,about 250, about 500, about 1000 or more times greater than the affinityfor a non-target.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is the enzymepoly(ADP-ribose)polymerase (PARP).

As used herein, the terms “treating” or “treatment” encompass either orboth responsive and prophylaxis measures, e.g., designed to inhibit,slow or delay the onset of a symptom of a disease or disorder, achieve afull or partial reduction of a symptom or disease state, and/or toalleviate, ameliorate, lessen, or cure a disease or disorder and/or itssymptoms.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening of severity, delay in onset, slowing ofprogression, or shortening of duration, whether permanent or temporary,lasting or transient that can be attributed to or associated withadministration of the compound or composition.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator includes a compoundthat causes an increase or a decrease in the magnitude of a certainactivity of a molecule compared to the magnitude of the activity in theabsence of the modulator. In certain embodiments, a modulator is aninhibitor, which decreases the magnitude of one or more activities of amolecule. In certain embodiments, an inhibitor completely prevents oneor more activities of a molecule. In certain embodiments, a modulator isan activator, which increases the magnitude of at least one activity ofa molecule. In certain embodiments the presence of a modulator resultsin an activity that does not occur in the absence of the modulator.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity.

As used herein, the term “PARP” refers to the family of the enzymepoly(ADP-ribose)polymerase which includes approximately 18 proteins,particularly poly(ADP-ribose)polymerase-1 (PARP-1) andpoly(ADP-ribose)polymerase-2 (PARP-2).

As used herein, the term “selective PARP modulator” refers to a compoundthat selectively modulates at least one activity associated with theenzyme poly(ADP-ribose)polymerase (PARP). In various embodiments, theselective modulator selectively modulates the activity of PARP-1,PARP-2, both PARP-1 and PARP-2 or several members of the family of theenzyme poly(ADP-ribose)polymerase (PARP).

As used herein, the term “method of inhibiting PARP” refers to a methodof inhibiting the activity of either one or more of the family of enzymepoly(ADP-ribose)polymerase (PARP). As used herein, the term “inhibitionof PARP” refers to inhibition of the activity of either one or more ofthe family of enzyme poly(ADP-ribose)polymerase (PARP).

As used herein, the term “modulating the activity of the enzymepoly(ADP-ribose)polymerase” refers to a modulating the activity ofeither one or more of the family of enzyme poly(ADP-ribose)polymerase(PARP).

As used herein, the term “selectively modulates” refers to the abilityof a selective modulator to modulate a target activity to a greaterextent than it modulates a non-target activity. In certain embodimentsthe target activity is selectively modulated by, for example about 2fold up to more that about 500 fold, in some embodiments, about 2, 5,10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or more than 500 fold.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, PARP.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” or “inhibitor” refers to acompound, the presence of which results in a decrease in the magnitudeof a biological activity of a protein. In certain embodiments, thepresence of an antagonist results in complete inhibition of a biologicalactivity of a protein, such as, for example, the enzymepoly(ADP-ribose)polymerase (PARP).

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of PARP, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

The term “cancer”, as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but are not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents include chemicalsused to stabilize compounds because they provide a more stableenvironment. Salts dissolved in buffered solutions (which also canprovide pH control or maintenance) are utilized as diluents in certainembodiments, including, but not limited to a phosphate buffered salinesolution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is determinedusing any suitable technique, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “enzymatically cleavable linker,” as used herein refers tounstable or degradable linkages which are degraded by one or moreenzymes.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain (dolor, fromthe generation of noxious substances and the stimulation of nerves),heat (calor, from vasodilatation), redness (rubor, from vasodilatationand increased blood flow), swelling (tumor, from excessive inflow orrestricted outflow of fluid), and loss of function (functio laesa, whichmay be partial or complete, temporary or permanent). Inflammation takesmany forms and includes, but is not limited to, inflammation that is oneor more of the following: acute, adhesive, atrophic, catarrhal, chronic,cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing,focal, granulomatous, hyperplastic, hypertrophic, interstitial,metastatic, necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative. Inflammatory disorders further include, without beinglimited to those affecting the blood vessels (polyarteritis, temporalarteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive,rheumatoid, Reiter's); gastrointestinal tract (Chrohn's Disease,ulcerative colitis); skin (dermatitis); or multiple organs and tissues(systemic lupus erythematosus).

The term “PARP-mediated”, as used herein, refers to conditions ordisorders that are ameliorated by the one or more of the family ofenzyme poly(ADP-ribose)polymerase (PARP).

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, in certain instances, enzymes produce specificstructural alterations to a compound. In some embodiments, metabolitesof the compounds disclosed herein are identified either byadministration of compounds to a host and analysis of tissue samplesfrom the host, or by incubation of compounds with hepatic cells in vitroand analysis of the resulting compounds.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

By “pharmaceutically acceptable” or “therapeutically acceptable”, asused herein, refers a material, such as a carrier or diluent, which doesnot abrogate the biological activity or properties of the compound, andis relatively nontoxic. In certain instances, nontoxic andnon-abrogative materials includes materials that when administered to anindividual do not cause substantial, undesirable biological effectsand/or do not interact in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” or “therapeuticallyacceptable salt”, refers to a formulation of a compound that does notcause significant irritation to an organism to which it is administeredand does not abrogate the biological activity and properties of thecompound. In certain instances, pharmaceutically acceptable salts areobtained by reacting a compound described herein, with acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they areeasier to administer than the parent drug. In certain instances, aprodrug is bioavailable by oral administration whereas the parent isnot. In some instances, a prodrug has improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug is a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid or amino group where the peptide ismetabolized to reveal the active moiety. In certain embodiments, upon invivo administration, a prodrug is chemically converted to thebiologically, pharmaceutically or therapeutically more active form ofthe compound. In certain embodiments, a prodrug is enzymaticallymetabolized by one or more steps or processes to the biologically,pharmaceutically or therapeutically active form of the compound. Toproduce a prodrug, a pharmaceutically active compound is modified suchthat the active compound will be regenerated upon in vivoadministration. In some embodiments, the prodrug is designed to alterthe metabolic stability or the transport characteristics of a drug, tomask side effects or toxicity, to improve the flavor of a drug or toalter other characteristics or properties of a drug.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Composition/Formulation

In certain embodiments, pharmaceutical compositions are formulated inany manner, including using one or more physiologically acceptablecarriers comprising excipients and/or auxiliaries which facilitateprocessing of the active compounds into pharmaceutical preparations. Insome embodiments, proper formulation is dependent upon the route ofadministration chosen. In various embodiments, any techniques, carriers,and excipients are used as suitable.

Provided herein are pharmaceutical compositions that include a compounddescribed herein and a pharmaceutically acceptable diluent(s),excipient(s), and/or carrier(s). In addition, in some embodiments, thecompounds described herein are administered as pharmaceuticalcompositions in which compounds described herein are mixed with otheractive ingredients, as in combination therapy.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In certain embodiments, apharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, includes administering or using a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundprovided herein. In specific embodiments, the methods of treatmentprovided for herein include administering such a pharmaceuticalcomposition to a mammal having a disease or condition to be treated. Inone embodiment, the mammal is a human. In some embodiments, thetherapeutically effective amount varies widely depending on the severityof the disease, the age and relative health of the subject, the potencyof the compound used and other factors. In various embodiments, thecompounds described herein are used singly or in combination with one ormore therapeutic agents as components of mixtures.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated for intravenous injections. In certain aspects, theintravenous injection formulations provided herein are formulated asaqueous solutions, and, in some embodiments, in physiologicallycompatible buffers such as Hank's solution, Ringer's solution, orphysiological saline buffer. In certain embodiments, the pharmaceuticalcompositions provided herein are formulated for transmucosaladministration. In some aspects, transmucosal formulations includepenetrants appropriate to the barrier to be permeated. In certainembodiments, the pharmaceutical compositions provided herein areformulated for other parenteral injections, appropriate formulationsinclude aqueous or nonaqueous solutions, and in one embodiment, withphysiologically compatible buffers or excipients.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated for oral administration. In certain aspects, the oralformulations provided herein comprise compounds described herein thatare formulated with pharmaceutically acceptable carriers or excipients.Such carriers enable the compounds described herein to be formulated astablets, powders, pills, dragees, capsules, liquids, gels, syrups,elixirs, slurries, suspensions and the like, for oral ingestion by apatient to be treated.

In some embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are optionally added, such as thecross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate.

In certain embodiments, provided herein is a pharmaceutical compositionformulated as dragee cores with suitable coatings. In certainembodiments, concentrated sugar solutions are used in forming thesuitable coating, and optionally contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. In some embodiments, dyestuffs and/or pigments are added totablets, dragees and/or the coatings thereof for, e.g., identificationor to characterize different combinations of active compound doses.

In certain embodiments, pharmaceutical preparations which are usedinclude orally include push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In some embodiments, the push-fit capsules containthe active ingredients in admixture with filler such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In certain embodiments, in soft capsules,the active compounds are dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers are optionally added. In certain embodiments, theformulations for oral administration are in dosages suitable for suchadministration.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated for buccal or sublingual administration. In certainembodiments, buccal or sublingual compositions take the form of tablets,lozenges, or gels formulated in a conventional manner. In certainembodiments, parenteral injections involve bolus injection or continuousinfusion. In some embodiments, formulations for injection are presentedin unit dosage form, e.g., in ampoules or in multi-dose containers, withan added preservative. In some embodiments, the pharmaceuticalcomposition described herein is in a form suitable for parenteralinjection as a sterile suspensions, solutions or emulsions in oily oraqueous vehicles, and optionally contains formulatory agents such assuspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. In some embodiments,suspensions of the active compounds are prepared as appropriate oilyinjection suspensions. Suitable lipophilic solvents or vehicles includefatty oils such as sesame oil, or synthetic fatty acid esters, such asethyl oleate or triglycerides, or liposomes. In certain embodiments,aqueous injection suspensions contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspensions also contain suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions. Inalternative embodiments, the active ingredient is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In some embodiments, the compounds described herein are administeredtopically. In specific embodiments, the compounds described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand/or preservatives.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated for transdermal administration of compounds describedherein. In some embodiments, administration of such compositions employstransdermal delivery devices and transdermal delivery patches. Incertain embodiments, the compositions are lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. Such patches include those constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. In someembodiments, transdermal delivery of the compounds described herein isaccomplished by use of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of thecompounds provided herein, such as, for example, compounds of Formula(I), (IA) or (II). In certain embodiments, the rate of absorption isslowed by using rate-controlling membranes or by trapping the compoundwithin a polymer matrix or gel. Conversely, absorption enhancers areoptionally used to increase absorption. Absorption enhancer and carrierinclude absorbable pharmaceutically acceptable solvents that assist inpassage of the compound through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated for administration by inhalation. In certain embodiments,in such pharmaceutical compositions formulated for inhalation, thecompounds described herein are in a form as an aerosol, a mist or apowder. In some embodiments, pharmaceutical compositions describedherein are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In certain aspects of a pressurized aerosol, thedosage unit is determined by providing a valve to deliver a meteredamount. In certain embodiments, capsules and cartridges of, such as, byway of example only, gelatin for use in an inhaler or insufflator isformulated containing a powder mix of the compound described herein anda suitable powder base such as lactose or starch.

In some embodiments, the compounds described herein are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas. Incertain embodiments, rectal compositions optionally contain conventionalsuppository bases such as cocoa butter or other glycerides, as well assynthetic polymers such as polyvinylpyrrolidone, PEG, and the like. Incertain suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

In various embodiments provided herein, the pharmaceutical compositionsare formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopharmaceutically acceptable preparations. In certain embodiments, properformulation is dependent upon the route of administration chosen. Invarious embodiments, any of the techniques, carriers, and excipients isused as suitable. In some embodiments, pharmaceutical compositionscomprising a compound described herein are manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

In certain embodiments, the pharmaceutical compositions include at leastone pharmaceutically acceptable carrier, diluent or excipient and acompound described herein described herein as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds described hereinexist as tautomers. All tautomers are included within the scope of thecompounds presented herein. Additionally, included herein are thesolvated and unsolvated forms of the compounds described herein.Solvated compounds include those that are solvated with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In some embodiments, the pharmaceutical compositionsdescribed herein include other medicinal or pharmaceutical agents,carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In additional embodiments, the pharmaceuticalcompositions described herein also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions containing the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. In various embodiments, thecompositions are in liquid solutions or suspensions, solid formssuitable for solution or suspension in a liquid prior to use, or asemulsions. These compositions optionally contain minor amounts ofnontoxic, auxiliary substances, such as wetting or emulsifying agents,pH buffering agents, and so forth.

In some embodiments, a composition comprising a compound describedherein takes the form of a liquid where the agents are present insolution, in suspension or both. In some embodiments, when thecomposition is administered as a solution or suspension a first portionof the agent is present in solution and a second portion of the agent ispresent in particulate form, in suspension in a liquid matrix. In someembodiments, a liquid composition includes a gel formulation. In otherembodiments, the liquid composition is aqueous.

Useful aqueous suspension optionally contain one or more polymers assuspending agents. Useful polymers include water-soluble polymers suchas cellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Useful compositions optionally comprise an mucoadhesivepolymer, selected for example from carboxymethylcellulose, carbomer(acrylic acid polymer), poly(methylmethacrylate), polyacrylamide,polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginateand dextran.

Useful compositions optionally include solubilizing agents to aid in thesolubility of a compound described herein. The term “solubilizing agent”generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Solubilizing agents includecertain acceptable nonionic surfactants, for example polysorbate 80, andophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400, and glycol ethers.

Useful compositions optionally include one or more pH adjusting agentsor buffering agents, including acids such as acetic, boric, citric,lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Useful compositions optionally include one or more salts in an amountrequired to bring osmolality of the composition into an acceptablerange. Such salts include those having sodium, potassium or ammoniumcations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Certain useful compositions optionally include one or more preservativesto inhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Some useful compositions optionally include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Certain useful compositions optionally one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In some embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. In alternative embodiments,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In various embodiments, any delivery system for hydrophobicpharmaceutical compounds is employed. Liposomes and emulsions areexamples of delivery vehicles or carriers for hydrophobic drugs. Incertain embodiments, certain organic solvents such asN-methylpyrrolidone are employed. In some embodiments, the compounds aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are utilized in the embodimentsherein. In certain embodiments, sustained-release capsules release thecompounds for a few weeks up to over 100 days. In some embodiments,depending on the chemical nature and the biological stability of thetherapeutic reagent, additional strategies for protein stabilization areemployed.

In certain embodiments, the formulations or compositions describedherein benefit from and/or optionally comprise antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In certain embodiments, the compounds described herein are used in thepreparation or manufacture of medicaments for the treatment of diseasesor conditions that are mediated by the enzyme poly(ADP-ribose)polymerase(PARP) or in which inhibition of the enzyme poly(ADP-ribose)polymerase(PARP) ameliorates the disease or condition. In some embodiments, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofpharmaceutical compositions containing at least one compound describedherein, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable N-oxide, pharmaceutically active metabolite, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest thesymptoms of the disease or condition. In some embodiments, amountseffective for this use will depend on the severity and course of thedisease or condition, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingphysician. In certain instances, it is considered appropriate for thecaregiver to determine such therapeutically effective amounts by routineexperimentation (including, but not limited to, a dose escalationclinical trial).

In certain prophylactic applications, compositions containing thecompounds described herein are administered to a patient susceptible toor otherwise at risk of a particular disease, disorder or condition. Insome embodiments, the amount administere is defined to be a“prophylactically effective amount or dose.” In certain embodiments ofthis use, the precise amounts of compound administered depend on thepatient's state of health, weight, and the like. In some embodiments, itis considered appropriate for the caregiver to determine suchprophylactically effective amounts by routine experimentation (e.g., adose escalation clinical trial). In certain embodiments, when used in apatient, effective amounts for this use will depend on the severity andcourse of the disease, disorder or condition, previous therapy, thepatient's health status and response to the drugs, and the judgment ofthe treating physician.

In certain instances, a patient's condition does not improve or does notsignificantly improve following administration of a compound orcomposition described herein and, upon the doctor's discretion theadministration of the compounds is optionally administered chronically,that is, for an extended period of time, including throughout theduration of the patient's life in order to ameliorate or otherwisecontrol or limit the symptoms of the patient's disease or condition.

In certain cases wherein the patient's status does improve or does notsubstantially improve, upon the doctor's discretion the administrationof the compounds are optionally given continuously; alternatively, thedose of drug being administered is optionally temporarily reduced ortemporarily suspended for a certain length of time (i.e., a “drugholiday”). In certain embodiments, the length of the drug holiday variesbetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday includes a reductionfrom about 10% to about 100%, including, by way of example only, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

In certain embodiments, once improvement of the patient's conditions hasoccurred, a maintenance dose is administered if necessary. In someembodiments, the dosage, e.g., of the maintenance dose, or the frequencyof administration, or both, are reduced, as a function of the symptoms,to a level at which the improved disease, disorder or condition isretained. In certain embodiments, however, patients are optionally givenintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

In certain embodiments, the amount of a given agent that corresponds toan effective amount varies depending upon factors such as the particularcompound, disease or condition and its severity, the identity (e.g.,weight) of the subject or host in need of treatment. In someembodiments, the effective amount is, nevertheless, determined accordingto the particular circumstances surrounding the case, including, e.g.,the specific agent that is administered, the route of administration,the condition being treated, and the subject or host being treated. Incertain embodiments, however, doses employed for adult human treatmentis in the range of about 0.02 to about 5000 mg per day, in a specificembodiment about 1 to about 1500 mg per day. In various embodiments, thedesired dose is conveniently presented in a single dose or as divideddoses administered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In some embodiments, the pharmaceutical compositions described hereinare in a unit dosage form suitable for single administration of precisedosages. In some instances, in unit dosage form, the formulation isdivided into unit doses containing appropriate quantities of one or morecompound. In certain embodiments, the unit dosage is in the form of apackage containing discrete quantities of the formulation. Non-limitingexamples are packaged tablets or capsules, and powders in vials orampoules. In some embodiments, aqueous suspension compositions arepackaged in single-dose non-reclosable containers. In alternativeembodiments, multiple-dose reclosable containers are used, in which caseit is typical to include a preservative in the composition. By way ofexample only, formulations for parenteral injection are, in someembodiments, presented in unit dosage form, which include, but are notlimited to ampoules, or in multi-dose containers, with an addedpreservative.

In certain embodiments, the daily dosages appropriate for the compoundsdescribed herein described herein are from about 0.01 to about 2.5 mg/kgper body weight. In some embodiments, an indicated daily dosage in thelarger subject, including, but not limited to, humans, is in the rangefrom about 0.5 mg to about 100 mg, conveniently administered in divideddoses, including, but not limited to, up to four times a day or inextended release form. In certain embodiments, suitable unit dosageforms for oral administration comprise from about 1 to about 50 mgactive ingredient. The foregoing ranges are merely suggestive, as thenumber of variables in regard to an individual treatment regime islarge, and considerable excursions from these recommended values are notuncommon. In certain embodiments, the dosages are altered depending on anumber of variables, not limited to the activity of the compound used,the disease or condition to be treated, the mode of administration, therequirements of the individual subject, the severity of the disease orcondition being treated, and the judgment of the practitioner.

In certain embodiments, toxicity and therapeutic efficacy of suchtherapeutic regimens are determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, the determination of the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratiobetween LD₅₀ and ED₅₀. In certain embodiments, compounds exhibiting hightherapeutic indices are preferred. In some embodiments, the dataobtained from cell culture assays and animal studies is used informulating a range of dosage for use in human. In specific embodiments,the dosage of such compounds lies within a range of circulatingconcentrations that include the ED₅₀ with minimal toxicity. In certainembodiments, the dosage varies within this range depending upon thedosage form employed and the route of administration utilized.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein is inflammation,then, in some embodiments, it is appropriate to administer ananti-inflammatory agent in combination with the initial therapeuticagent. In some embodiments, the therapeutic effectiveness of one of thecompounds described herein is enhanced by administration of an adjuvant(i.e., in some embodiments, by itself the adjuvant has minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced). In certainembodiments, the benefit experienced by a patient is increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In some embodiments, regardless of the disease,disorder or condition being treated, the overall benefit experienced bythe patient as a result of a combination treatment is additive orsynergistic.

In certain embodiments, therapeutically-effective dosages vary when thedrugs are used in treatment combinations. In some embodiments,therapeutically-effective dosages of drugs and other agents for use incombination treatment regimens is determined in any suitable manner,e.g., through the use of metronomic dosing, i.e., providing morefrequent, lower doses in order to minimize toxic side effects. In someembodiments, combination treatment regimen described herein encompasstreatment regimens in which administration of a PARP inhibitor describedherein is initiated prior to, during, or after treatment with a secondagent described above, and continues until any time during treatmentwith the second agent or after termination of treatment with the secondagent. It also includes treatments in which a PARP inhibitor describedherein and the second agent being used in combination are administeredsimultaneously or at different times and/or at decreasing or increasingintervals during the treatment period. Combination treatment furtherincludes periodic treatments that start and stop at various times toassist with the clinical management of the patient. For example, in someembodiments, a PARP inhibitor described herein in the combinationtreatment is administered weekly at the onset of treatment, decreasingto biweekly, and decreasing further as appropriate.

In certain embodiments, compositions and methods for combination therapyare provided herein. In accordance with one aspect, the pharmaceuticalcompositions disclosed herein are used to in a method of treating a PARPmediated disease or condition or a disease or condition that isameliorated by inhibition of PARP. In accordance with certain aspects,the pharmaceutical compositions disclosed herein are used to treatvascular disease; septic shock; ischaemic injury; reperfusion injury;neurotoxicity; hemorrhagic shock; inflammatory diseases; multiplesclerosis; secondary effects of diabetes; and acute treatment ofcytotoxicity following cardiovascular surgery. In a certain aspect, thepharmaceutical compositions disclosed herein are used in combination,either simultaneously or sequentially, with ionizing radiation or one ormore chemotherapeutic agents.

In certain embodiments, combination therapies described herein are usedas part of a specific treatment regimen intended to provide a beneficialeffect from the co-action of a PARP inhibitor described herein and aconcurrent treatment. It is understood that the dosage regimen to treat,prevent, or ameliorate the condition(s) for which relief is sought, isoptionally modified in accordance with a variety of factors.

In certain combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In some embodiments, when co-administeredwith one or more biologically active agents, the compound providedherein is administered either simultaneously with the biologicallyactive agent(s), or sequentially. In certain aspects wherein the agentsare administered sequentially, the attending physician will decide onthe appropriate sequence of administering protein in combination withthe biologically active agent(s).

In various embodiments, the multiple therapeutic agents (one of which isone of the compounds described herein) are administered in any order oreven simultaneously. In certain instances, administration issimultaneous and the multiple therapeutic agents are, optionally,provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). In someembodiments, one of the therapeutic agents is given in multiple doses,or both are given as multiple doses. In some instances, administrationis not simultaneous and the timing between the multiple doses varies, byway of non-limiting example, from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

In additional embodiments, the compounds described herein are used incombination with procedures that provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

In certain embodiments, the compounds described herein and combinationtherapies are administered before, during or after the occurrence of adisease or condition. In certain embodiments, the timing ofadministering the composition containing a compound varies. Thus, forexample, in some embodiments, the compounds are used as a prophylacticand are administered continuously to subjects with a propensity todevelop conditions or diseases in order to prevent the occurrence of thedisease or condition. In some embodiments, the compounds andcompositions are administered to a subject during or as soon as possibleafter the onset of the symptoms. In certain embodiments, theadministration of the compounds is initiated within the first 48 hoursof the onset of the symptoms, within the first 6 hours of the onset ofthe symptoms, or within 3 hours of the onset of the symptoms. Theinitial administration is achieved via any route practical, such as, forexample, an intravenous injection, a bolus injection, infusion over 5minutes to about 5 hours, a pill, a capsule, transdermal patch, buccaldelivery, and the like, or combination thereof. In some embodiments, acompound is administered as soon as is practicable after the onset of adisease or condition is detected or suspected, and for a length of timenecessary for the treatment of the disease, such as, from about 1 monthto about 3 months. In certain embodiments, the length of treatmentvaries for each subject, and the length is determined using anycriteria. In exemplary embodiments, a compound or a formulationcontaining the compound is administered for at least 2 weeks, for about1 month to about 5 years, or for about 1 month to about 3 years.

Other Combination Therapies

In certain embodiments described herein, methods for treatment of PARPmediated conditions or diseases, such as proliferative disorders,including cancer, include administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from the groupconsisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated ornon-), bevacizumab, cetuximab, platinum-based compounds such ascisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel,taxol, temozolomide, thioguanine, or classes of drugs including hormones(an antiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, and dronabinol.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. In variousembodiments, such kits comprise a carrier, package, or container that iscompartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) comprising one of theseparate elements to be used in a method described herein. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. In some embodiments, the containers are formed from a variety ofmaterials such as glass or plastic.

In some embodiments, the articles of manufacture provided herein containpackaging materials. Packaging materials for use in packagingpharmaceutical products include, but are not limited to, blister packs,bottles, tubes, inhalers, pumps, bags, vials, containers, syringes,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment.

In some embodiments, the container(s) described herein comprise one ormore compounds described herein, optionally in a composition or incombination with another agent as disclosed herein. The container(s)optionally have a sterile access port (for example in some embodimentsthe container is an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). Such kits optionallycomprise a compound with an identifying description or label orinstructions relating to its use in the methods described herein.

In some embodiments, a kit will comprises one or more additionalcontainers, each with one or more of various materials (such asreagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound describedherein. Non-limiting examples of such materials include, but are notlimited to, buffers, diluents, filters, needles, syringes; carrier,package, container, vial and/or tube labels listing contents and/orinstructions for use, and package inserts with instructions for use. Aset of instructions is optionally included.

In certain embodiments, a label is on or associated with the container.In some embodiments, a label is on a container when letters, numbers orother characters forming the label are attached, molded or etched intothe container itself; a label is associated with a container when it ispresent within a receptacle or carrier that also holds the container,e.g., as a package insert. In certain embodiments, a label indicatesthat the contents are to be used for a specific therapeutic application.In some embodiments, the label indicates directions for use of thecontents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions are presented ina pack or dispenser device which contains one or more unit dosage formscontaining a compound provided herein. In some embodiments, the packcontains a metal or plastic foil, such as a blister pack. The pack ordispenser device is optionally accompanied by instructions foradministration. In some embodiments, the pack or dispenser isaccompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for human or veterinary administration.In certain embodiments, such notice is, for example, the labelingapproved by the U.S. Food and Drug Administration for prescriptiondrugs, or the approved product insert. In some embodiments, compositionscontaining a compound provided herein are formulated in a compatiblepharmaceutical carrier and are placed in an appropriate containerlabeled for treatment of an indicated condition.

EXAMPLES

The following Examples are intended as an illustration of the variousembodiments as defined in the appended claims. In some embodiments, thecompounds are prepared by a variety of synthetic routes. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference for all purposes.

Example 1 Example 1a: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound described herein is dissolved in DMSO and then mixed with 10 mLof 0.9% sterile saline. The mixture is incorporated into a dosage unitform suitable for administration by injection.

Example 1b: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound described herein is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 1c: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound described herein, with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 1d: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound described herein is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 1e: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound described herein is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Example 1f: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound described herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Example 1g: Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound described herein is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Example 28,9-Diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one Example2A 4-Nitroisobenzofuran-1(3H)-one

A suspension of sodium borohydride (0.757 g, 20 mmol) in anhydroustetrahydrofuran (120 mL) was cooled to 0° C. A solution of4-nitrobenzofuran-1,3-dione (6.18 g, 32 mmol) in anhydroustetrahydrofuran (30 mL) was then added dropwise to the suspension. Afterthe addition, the mixture was allowed to stir at this temperature for 3hr. The reaction was quenched with 3N hydrochloric acid (to pH=1). Water(40 mL) was added to the mixture and stirred for 1 hr. Tetrahydrofuranwas removed under reduced pressure. The residue was partioned betweenwater (150 mL) and ethyl acetate (150 mL×3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate,concentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 2:1)to give 4-nitroisobenzofuran-1(3H)-one (4.2 g, yield 73%) as a whitesolid. MS (ESI) m/z: 180 (M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) δ □5.77 (s,3H), 7.32-7.34 (d, J=8.4 Hz, 1H), 7.81-7.85 (t, J=8.0 Hz, 1H), 8.29 (d,J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H).

Example 2B 4-Aminoisobenzofuran-1(3H)-one

A suspension of 4-nitroisobenzofuran-1(3H)-one (1.0 g, 5.58 mmol) and10% Pd/C (0.1 g) in ethyl acetate (30 mL) was purged in 1 atm hydrogenand stirred at 25° C. for 3 hr. The mixture was filtered, and thefiltrate was concentrated to give 4-aminoisobenzofuran-1(3H)-one (0.8 g,yield 96%) as a off-white solid. MS (ESI) m/z: 150 (M+1)⁺. ¹H-NMR (400MHz, CDCl₃) □□δ 3.82 (s, br 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H),7.32-7.36 (m, 2H).

Example 2C Methyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (0.4 g, 2.68 mmol) andbenzaldehyde (0.72 g, 6.7 mmol) in ethyl propionate (20 mL) was cooledto 0° C. Then a solution of sodium methoxide in methanol [sodium (248mg, 10.72 mmol) in methanol (20 mL)] was added dropwise. After theaddition, the mixture was heated at reflux for 16 hr. The mixture wasquenched with water (10 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, acidified with 1N hydrochloric acid topH=6, then extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified byprep-HPLC to give methyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (256 mg,yield 27%) and ethyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg,yield 14%) as a light yellow solid. Methyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate: MS (ESI)m/z: 358 (M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) □□δ 3.86 (s, 3H), 3.95-3.98 (d,J=16.4 Hz, 1H), 4.81-4.84 (d, J=12.8 Hz, 1H), 4.89 (s, br 1H), 6.72-6.77(m, 2H), 6.90-6.93 (m, 2H), 7.11-7.21 (m, 8H), 7.34-7.36 (t, J=7.8 Hz,1H).

Example 2D8,9-Diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg,mmol) in hydrazine monohydrate (25 mL) was heated to reflux for 20 hr.The mixture was diluted with water (30 mL), extracted with ethyl acetate(30 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give crude product.The crude product was purified by chromatography (silica gel, petroleumether/ethyl acetate=20:1 to 8:1) to give8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15.6mg, yield 16%) as a white solid. MS (ESI) m/z: 340 (M+1)⁺. ¹H-NMR (400MHz, CDCl₃) δ □4.22-4.25 (d, J=9.6 Hz, 1H), 4.66-4.69 (d, J=9.6 Hz, 1H),7.02-7.06 (m, 3H), 7.16-7.26 (m, 8H), 7.57-7.61 (t, J=7.8 Hz, 1H),7.74-7.76 (d, J=7.6 Hz, 1H), 9.82 (s, 1H).

Example 38,9-Bis(4-(methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 3A Methyl2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 mmol) and4-(diethoxymethyl)benzaldehyde (1.04 g, 5 mmol) in ethyl propionate (15mL) was cooled to 0° C. A solution of sodium methoxide in methanol[sodium (184 mg, 8 mmol) in methanol (15 mL)] was then added dropwise.After the addition, the mixture was stirred at 25° C. for 16 hr. Themixture was quenched with water (10 mL) and solvent was removed invacuum. The residue was dissolved in water, and then extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to givecrude product. The crude product was purified by chromatography (silicagel, petroleum ether/ethyl acetate=100:1 to 10:1) to give methyl2,3-bis(4(-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(4(-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(240 mg together, yield 21%) as a light yellow solid. LC-MS (ESI) m/z:562 (M+1)⁺ (methyl2,3-bis(4(-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate);576 (M+1)⁺ (ethyl2,3-bis(4(-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate).

Example 3B8,9-Bis(4-(diethoxymethyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(240 mg, 0.43 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL)was stirred at 40° C. for 2 hr. The mixture was cooled to roomtemperature and filtered to give the8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, yield 52%) as a light yellow solid. LC-MS (ESI) m/z: 544(M+1)⁺. MS (ESI) m/e 381 [M+H]⁺.

Example 3C4,4′-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde

A mixture of8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, 0.22 mmol) in 3N hydrochloric acid (5 mL) was stirred at roomtemperature for 3 hr. Then the mixture was neutralized (basified) withpotassium carbonate to pH=8. The resulting suspension was filtered togive4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde(80 mg, yield 97%) as a light yellow solid. LC-MS (ESI) m/z: 396 (M+1)⁺.

Example 3DBis(4-(methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(71i)-one

A mixture of4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde(80 mg, 0.21 mmol) and 27% methylamine alcohol solution (94 mg, 0.82mmol) in methanol (10 mL) was stirred at room temperature for 40 min.The mixture was then cooled to 0° C. Sodium borohydride (24 mg, 0.64mmol) was added. After the addition, the mixture was stirred at roomtemperature for 4 hr. Methanol was removed under reduced pressure. Theresidue was washed with ethyl acetate and filtered. The filtrate wasconcentrated to give8,9-bis(4-(methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(29.5 mg, yield 33%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆)δ □2.20 (d, J=8.8 Hz, 6H), 3.52-3.53 (d, J=2.4 Hz, 4H), 4.31-4.33 (d,J=6.4 Hz, 1H), 4.76-4.77 (d, J=6.4 Hz, 1H), 7.06-7.08 (d, J=6.4 Hz, 2H),7.12-7.17 (m, 5H), 7.35-7.38 (t, J=6.4 Hz, 2H), 7.49-7.57 (t, J=10.0 Hz,1H); LC-MS (ESI) m/z: 426 (M+1)⁺.

Example 48,9-Di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 4A Methyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (149 mg, 1 mmol) andnicotinaldehyde (268 mg, 2.5 mmol) in ethyl propionate (10 mL) wascooled to 0° C. Then a solution of sodium methoxide in methanol [sodium(93 mg, 4 mmol) in methanol (3 mL)] was added dropwise. After theaddition, the mixture was stirred at 25° C. for 16 hr. The mixture wasquenched with water (5 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give crude product.The crude product was purified by prep-HPLC to give methyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (60mg, yield 17%) and ethyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (4mg, yield 1%) as a light yellow solid. LC-MS (ESI) m/z: 360(M+1)⁺(methyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate),374 (M+1)⁺ (ethyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate).

Example 4B8,9-Di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (60mg, 0.17 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for4 hr. Then the mixture was cooled to room temperature and solvent wasremoved in vacuum to give crude product. The crude product was purifiedby pre-HPLC to give8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(15 mg, yield 68%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO) δ□4.46-4.48 (d, J=8.4 Hz, 1H), 4.90-4.92 (d, J=8.4 Hz, 1H), 7.16-7.20 (m,3H), 7.32-7.34 (d, J=5.2 Hz, 2H), 7.40-7.42 (d, J=8.4 Hz, 1H), 7.55 (s,1H), 7.59-7.63 (t, J=8.0 Hz, 1H), 8.40-8.40 (d, J=5.2 Hz, 2H), 8.44-8.45(d, J=5.2 Hz, 2H). LC-MS (ESI) m/z: 342 (M+1)⁺.

Example 58,9-Di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 5A methyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 mmol) andnicotinaldehyde (535 mg, 5 mmol) in ethyl propionate (15 mL) was cooledto 0° C. A solution of sodium methoxide in methanol [sodium (184 mg, 8mmol) in methanol (15 mL)] was then added dropwise. After the addition,the mixture was stirred at 25° C. for 16 hr. The mixture was quenchedwith water (10 mL) and solvent was removed in vacuum. The residue wasdissolved in water, and then extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated to give crude product. The crudeproduct was purified by chromatography (silica gel, petroleumether/ethyl acetate=100:1 to 10:1) to give methyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(480 mg together, yield 67%) as a light yellow solid. LC-MS (ESI) m/z:360 (M+1)⁺(methyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate);374 (M+1)⁺ (ethyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate).

Example 5B8,9-Di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(480 mg, 1.34 mmol) in hydrazine monohydrate (20 mL) and methanol (5 mL)was heated to reflux for 2 hr. The mixture was then cooled to roomtemperature and filtered to give8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(320 mg, yield 68%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ□4.51-4.53 (d, J=8.4 Hz, 1H), 4.89-4.91 (d, J=8.4 Hz, 1H), 7.18-7.20 (m,1H), 7.24-7.27 (m, 1H), 7.31-7.33 (m, 1H), 7.43-7.44 (m, 1H), 7.60 (s,1H), 7.58-7.63 (m, 2H), 7.79-7.81 (m, 1H), 8.32-8.34 (m, 2H), 8.41-8.43(m, 1H), 8.45-8.46 (d, J=1.6 Hz, 1H); LC-MS (ESI) m/z: 342 (M+1)⁺.

Example 68,9-Di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 6A methyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (149 mg, 1 mmol) andnicotinaldehyde (268 mg, 2.5 mmol) in ethyl propionate (10 mL) wascooled to 0° C. A solution of sodium methoxide in methanol [sodium (93mg, 4 mmol) in methanol (3 mL)] was then added dropwise. After theaddition, the mixture was stirred at 25° C. for 16 hr. The mixture wasquenched with water (5 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give crude product.The crude product was purified by prep-HPLC to give methyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (72mg, yield 20%) and ethyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (14mg, yield 3%) as a light yellow solid. LC-MS (ESI) m/z: 360(M+1)⁺(methyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate);374 (M+1)⁺ (ethyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate).

Example 6B8,9-Di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate andethyl4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (68mg, 0.19 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for4 hr. Then the mixture was cooled to room temperature and solvent wasremoved in vacuum to give crude product. The crude product was purifiedby pre-HPLC to give8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(24 mg, yield 37%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO) δ□5.42-5.43 (d, J=5.2 Hz, 1H), 5.56-5.57 (d, J=5.2 Hz, 1H), 7.30-7.32 (d,J=8.0 Hz, 1H), 7.37-7.39 (d, J=8.0 Hz, 1H), 7.63-7.66 (t, J=6.6 Hz, 1H),7.68-7.70 (m, 2H), 7.78-7.80 (d, J=7.2 Hz, 1H), 7.87-7.89 (d, J=8.0 Hz,1H), 8.11-8.16 (m, 2H), 8.66-8.67 (d, J=4.8 Hz, 1H), 8.74-8.76 (d, J=5.6Hz, 1H); LC-MS (ESI) m/z: 342 (M+1)⁺.

Example 79-Isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 7A (E)-4-(Benzylideneamino)isobenzofuran-1(3H)-one

4-aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), benzaldehyde (427 mg, 4mmol) were added to methanol (20 mL) and stirred under reflux overnight,then the mixture was evaporated under reduced pressure and the residuewas dried in vacuum. 600 mg of crude product(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one was obtained which wasused for the next synthetic step without further purification.

Example 7B Methyl3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

4-(benzylideneamino)isobenzofuran-1(3H)-one (237 mg, 1 mmol),isobutyraldehyde (216 mg, 3 mmol), sodium methanolate (162 mg, 3 mmol)and ethyl propionate (20 mL) were added and the mixture was stirred atroom temperature overnight. Then the resulting mixture was evaporatedunder reduced pressure and extracted with ethyl acetate (100 mL×4) andconcentrated. The crude product was purified by column chromatography(silica gel, petroleum ether/ethyl acetate=20:1 to 5:1). 35 mg of solidmethyl-3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylatewas obtained. (yield: 11%). LC-MS (ESI) m/z: 308 (M+1)⁺.

Example 7C9-Isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (35mg, 1 mmol) and hydrazine monohydrate (20 mL) were added and the mixturewas stirred under 40° C. for 3 h. The resulting mixture was extractedwith ethyl acetate (100 mL×4) and concentrated, purified with prep-HPLC.7 mg of solid9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas obtained (yield: 15%). ¹H-NMR (400 MHz, DMSO-d₆): δ 0.82-0.83 (d,J=5.2 Hz, 3H), 1.15-1.17 (d, J=5.2 Hz, 3H), 1.89-1.93 (m, 1H), 2.71-2.73(d, J=6.0 Hz, 1H), 4.83 (s, 1H), 7.11-7.26 (m, 7H), 7.51-7.54 (m, 2H),12.11 (s, 1H). LC-MS (ESI) m/z: 306 (M+1)⁺.

Example 89-(4-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 8A 1-(4-(Diethoxymethyl)phenyl)-N-methylmethanamine

A mixture of 4-(diethoxymethyl)benzaldehyde (1.04 g, 5 mmol) andmethylamine (27˜32% solution in methanol, 2.3 g, 20 mmol) in methanol(20 mL) was stirred at room temperature for 40 mins. The mixture wascooled to 0° C., sodium borohydride (0.284 g, 7.5 mmol) was addedportionwise. After the addition, the mixture was stirred at roomtemperature for 4 hr. Methanol was removed under reduced pressure. Theresidue was partitioned between water (50 mL) and ethyl acetate (50 mL).The organic layer was separated. The aqueous layer was extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to givecrude 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g) as alight yellow oil which was used in the next step without furtherpurification. LC-MS (ESI) m/z: 224 (M+1)⁺.

Example 8B Benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate

To a stirred solution of1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g, 4.9 mmol) andtriethylamine (0.75 g, 7.35 mmol) in anhydrous dichloromethane (10 mL)was added benzyl carbonochloridate (1.0 g, 5.88 mmol) at 0° C. After theaddition, the mixture was allowed to stir at room temperature overnight.The mixture was diluted with dichloromethane (50 mL), washed with water(50 mL×3), brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated to give crude product which was purified by chromatography(silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give benzyl4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g, yield 57% for twosteps) as a light yellow oil. ¹H-NMR (400 MHz, CDCl₃) □□δ: 3.82 (s, br1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI)m/z: 358 (M+1)⁺.

Example 8C Benzyl 4-formylbenzyl(methyl)carbamate

The mixture of benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g,2.8 mmol) in 3N hydrochloric acid (50 ml) was stirring at roomtemperature for 1 h. Then the mixture was neutralized with Potassiumcarbonate. The resulting mixture was extracted with ethyl acetate (100mL×4), the organic phase was washed with water and saturated sodiumbicarbonate, dried with anhydrous sodium sulfate and concentrated togive benzyl 4-formylbenzyl(methyl)carbamate (730 mg, 92%). ¹H-NMR (400MHz, CDCl₃) □□δ: 2.94 (d, 3H), 4.572 (d, 2H), 5.18 (d, 2H), 7.32-7.39(m, 7H), 7.84 (m, 2H), 10.00 (s, 1H); LC-MS (ESI) m/z: 284 (M+1)⁺.

Example 8D Methyl3-(4-4(benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of benzyl 4-formylbenzyl(methyl)carbamate (566 mg, 2 mmol) and4-(benzylideneamino) isobenzofuran-1-one (474 mg, 2 mmol) in ethylpropionate (15 mL) was cooled to 0° C. A solution of sodium methoxide inmethanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then addeddropwise. After the addition, the mixture was stirred at 25° C. for 18hr. The mixture was quenched with water (10 mL) and solvent was removedin vacuum. The residue was dissolved in water, and then extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to givecrude product. The crude product was purified by chromatography (silicagel, petroleum ether/ethyl acetate=100:1 to 10:1) to give a mixture ofmethyl3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(220 mg, yield 20%) as a light yellow solid. LC-MS (ESI) m/z: 535 (M+1)⁺and 549 (M+1)⁺.

Example 8E Benzylmethyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate

A mixture of methyl3-(4-4(benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(220 mg, 0.94 mmol) in hydrazine monohydrate (50 mL) and methanol (5 mL)was stirred at 40° C. for 24 hr. The mixture was cooled to roomtemperature and filtered to give the crude product. The crude productwas purified by chromatography (silica gel, petroleum ether/ethylacetate=3:1) to give benzylmethyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate(80 mg, yield 16%). LC-MS (ESI) m/z: 517 (M+1)⁺.

Example 8F9-(4-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of benzylmethyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate(80 mg, 0.26 mmol), 10% Pd/C (20 mg) of methanol (50 ml) was stirring atroom temperature for 4 h. The mixture solution was then filtered andevaporated under reduced pressure. The residue was purified byprep-HPLC. 3 mg of9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand 6 mg of9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewere obtained, yield 9%. For9-(4-((methylamino)methyl)-phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ: 2.50 (s, 3H), 3.87 (s, 2H), 4.38 (d, 1H),4.75 (d, 1H), 7.15-7.17 (m, 2H), 7.19-7.25 (m, 5H), 7.27-7.28 (m, 3H),7.57 (d, 1H), 7.65 (t, 1H). LC-MS (ESI) m/z: 383 (M+1)⁺. For9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ: 2.31 (s, 6H), 3.57 (s, 2H), 4.33 (d, 1H),4.73 (d, 1H), 7.10-7.12 (m, 2H), 7.19-7.21 (m, 6H), 7.26-7.27 (m, 2H),7.58 (d, 1H), 7.64 (t, 1H). LC-MS (ESI) m/z: 397 (M+1)⁺.

Example 99-(3-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 9A

Methyl3-(3-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (474 mg, 2mmol) and 3-(diethoxymethyl)benzaldehyde (418 mg, 2 mmol) in ethylpropionate (20 mL) was cooled to 0° C. Sodium methoxide in methanolsolution [sodium (148 mg, 8 mmol) in methanol (2 mL)] was then addeddropwise and the mixture was stirred at room temperature overnight. Theresulting mixture was evaporated under reduced pressure. The residue wasextracted with ethyl acetate (100 mL×3) and the combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated to give crude product. The crude product was purified bycolumn chromatography (silica gel, petroleum ether/ethyl acetate=50:1 to5:1) to give methyl3-(3-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(230 mg, yield 25%) as a yellow solid.

Example 9B9-(3-(Diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl3-(3-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(300 mg, 0.65 mmol) in hydrazine monohydrate (20 mL) was stirred at 45°C. for 4 h. The resulting mixture was filtered to give9-(3-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(95 mg, yield 33%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ:□1.04-1.08 (t, J=7.0 Hz, 6H), 3.27-3.31 (q, 4H), 4.34-4.36 (d, J=8.8 Hz,1H), 4.74-4.76 (d, J=8.8 Hz, 1H), 5.34 (s, 1H), 7.08 (s, 1H), 7.14-7.24(m, 7H), 7.27-7.29 (m, 2H), 7.37-7.39 (d, J=7.2 Hz, 1H), 7.43 (s, 1H),7.56-7.60 (t, J=8.0 Hz, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 442 (M+1)⁺.

Example 9C3-(3-Oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde

A mixture of9-(3-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(90 mg, 0.20 mmol) in 3N hydrochloric acid (12 mL) was stirred at roomtemperature for 20 hr. Then the mixture was adjusted to pH=8 withpotassium carbonate. The resulting suspension was extracted with ethylacetate to give3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(66 mg, yield 88%) as a light yellow solid. LC-MS (ESI) m/z: 368 (M+1)⁺.

Example 9D9-(3-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(66 mg, 0.18 mmol) and 27% methylamine alcohol solution (83 mg, 0.72mmol) in methanol (15 mL) was stirred at room temperature for 1 h. Themixture was then cooled to 0° C. and sodium borohydride (11 mg, 0.27mmol) was added. After the addition, the mixture was stirred at roomtemperature for 4 hr. Methanol was removed under reduced pressure. Theresidue was purified by prep-HPLC to give9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(34 mg, yield 49%) as a light yellow solid. ¹H-NMR (400 MHz, MeOD-d4) δ:□2.55 (s, 3H), 4.04-4.13 (q, 2H), 4.36-4.38 (d, J=9.6 Hz, 1H), 4.74-4.76(d, J=8.8 Hz, 1H), 7.18-7.24 (m, 6H), 7.25-7.35 (m, 4H), 7.56-7.58 (d,J=7.6 Hz, 1H), 7.62-7.66 (t, J=8 Hz, 1H); LC-MS (ESI) m/z: 383 (M+1)⁺.

Example 108-(4-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 10A(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one

4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol),4-(ethoxy(methoxy)methyl) benzaldehyde (1.6 g, 8 mmol) and 1 g ofmagnesium sulfate were added into 40 mL of dichloromethane and stirredunder reflux overnight, then the mixture was evaporated under reducedpressure and the residue was dried in vacuum to give 600 mg of crudeproduct(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one whichwithout further purification was used in next step.

Example 10B Methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (600mg, 1 mmol), benzaldehyde (616 mg, 3 mmol), sodium methanolate (414 mg,7.6 mmol) and ethyl propionate (20 ml) were added and the mixture wasstirred at room temperature overnight. The resulting mixture was thenevaporated under reduced pressure and extracted with ethyl acetate (100mL×4) and concentrated. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate=20:1 to 5:1)to yield 120 mg of solid of methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(yield: 22%). LC-MS (ESI) m/z: 432 (M+1)⁺.

Example 10C8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg, 0.28 mmol) was added hydrazine monohydrate (20 mL) and themixture was stirred under 40° C. for 3 h. The resulting mixture wasevaporated under reduced pressure to 10 ml and then filtered, 89 mg ofsolid of8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas obtained (yield: 78%). LC-MS (ESI) m/z: 414 (M+1)⁺.

Example 10D4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

To8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(89 mg, 0.22 mmol) was added 20 ml of hydrochloric acid (3 mol/L) andthe mixture was stirred at room temperature for 2 h. The resultingmixture was evaporated under reduced pressure to 10 ml and thenfiltered, 59 mg of solid of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehydewas obtained; yield: 73%. LC-MS (ESI) m/z: 368 (M+1)⁺.

Example 10E8-(4-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(59 mg, 0.16 mmol) was added methanamine (20 ml) and the mixture wasstirred at room temperature for 2 h. Then 30 mg of sodium borohydridewas added and stirred for another 2 h. The resulting mixture wasevaporated under reduced pressure and purified by prep-HPLC. 11.5 mg of8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas obtained (yield: 19%). ¹H-NMR (400 MHz, CD₃OD) δ: 2.66 (s, 3H),4.33-4.35 (d, J=8 Hz, 1H), 4.83-4.85 (d, J=7.6 Hz, 1H), 7.10-7.12 (m,2H), 7.15-7.22 (m, 4H), 7.34-7.42 (m, 4H), 7.55-7.57 (m, 1H), 7.63-7.67(m, 1H). LC-MS (ESI) m/z: 383 (M+1)⁺.

Example 118,9-Bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 11A Methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 mmol) and3-(diethoxymethyl)benzaldehyde (0.83 g, 4 mmol) in ethyl propionate (15mL) was cooled to 0° C. Then a solution of sodium methoxide in methanol[sodium (184 mg, 8 mmol) in methanol (15 mL)] was added dropwise. Afterthe addition, the mixture was stirred at 25° C. for 18 hr. The mixturewas quenched with water (10 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give crude product.The crude product was purified by chromatography (silica gel, petroleumether/ethyl acetate=100:1 to 10:1) to give a mixture of methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(370 mg; yield 33%) as a light yellow solid. LC-MS (ESI) m/z: 562(M+1)⁺, and 576 (M+1)⁺.

Example 11B8,9-Bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL)was stirred at 40° C. for 2 hr. The mixture was cooled to roomtemperature and filtered to give8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(250 mg, yield 77%) as a light yellow solid. LC-MS (ESI) m/z: 544(M+1)⁺.

Example 11C3,3′-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde

A mixture of8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at roomtemperature for 3 hr. The mixture was then adjusted to pH=8 withpotassium carbonate. The resulting suspension was filtered to give3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde(160 mg, yield 88%) as a light yellow solid. LC-MS (ESI) m/z: 396(M+1)⁺.

Example 11D8,9-Bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde(100 mg, 0.25 mmol) and 27% methylamine alcohol solution (122 mg, 1.07mmol) in methanol (15 mL) was stirred at room temperature for 40 min.The mixture was then cooled to 0° C. Sodium borohydride (31 mg, 1.00mmol) was added. After the addition, the mixture was stirred at roomtemperature for 4 hr. Methanol was removed under reduced pressure. Theresidue was washed with ethyl acetate and filtered. The filtrate wasconcentrated to give8,9-bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(20 mg, yield 19%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) ≡:□2.62-2.63 (d, J=4.0 Hz, 6H), 4.12-4.13 (d, J=10.8 Hz, 4H), 4.42-4.44(d, J=8.4 Hz, 1H), 4.84-4.86 (d, J=8.4 Hz, 1H), 7.20-7.24 (m, 2H),7.29-7.33 (m, 6H), 7.52 (s, 1H), 7.57-7.60 (dd, J₁=8.0 Hz, J₂=1.2 Hz,1H), 7.65-7.69 (t, J=7.6 Hz, 1H); LC-MS (ESI) m/z: 426 (M+1)⁺.

Example 129-(4-(Hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 12A methyl3-(4-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl3-(4-(Diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (474 mg, 2mmol) and 4-(diethoxymethyl)benzaldehyde (0.40 g, 2.4 mmol) in ethylpropionate (15 mL) was cooled to 0° C. A solution of sodium methoxide inmethanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then addeddropwise. After the addition, the mixture was stirred at 25° C. for 18hr. The mixture was quenched with water (10 mL) and solvent was removedin vacuum. The residue was dissolved in water, and then extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to givecrude product. The crude product was purified by chromatography (silicagel, petroleum ether/ethyl acetate=100:1 to 10:1) to give methyl3-(4-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl3-(4-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(430 mg, yield: 47%) as a light yellow solid. LC-MS (ESI) m/z: 460(M+1)⁺ and 474 (M+1)⁺.

Example 12B9-(4-(Diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(4-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl3-(4-(diethoxymethyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(430 mg, 0.94 mmol) in hydrazine monohydrate (10 mL) and methanol (5 mL)was stirred at 40° C. for 24 hr. The mixture was cooled to roomtemperature and filtered to give the9-(4-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(270 mg, yield: 65%) as a light yellow solid. LC-MS (ESI) m/z: 442(M+1)⁺.

Example 12C4-(3-Oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde

A mixture of9-(4-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(270 mg, 0.61 mmol) in 3N hydrochloric acid (10 mL) was stirred at roomtemperature for 3 hr. The mixture was then adjusted to pH=8 withpotassium carbonate. The resulting suspension was filtered to give4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(140 mg, yield: 69%) as a light yellow solid.

Example 12D9-(4-(Hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(140 mg, 0.42 mmol) and 27% methylamine alcohol solution (194 mg, 1.69mmol) in methanol (15 mL) was stirred at room temperature for 40 min.Then the mixture was cooled to 0° C. Sodium borohydride (48 mg, 1.26mmol) was added. After the addition, the mixture was stirred at roomtemperature for 4 hr. TLC (petroleum ether/ethyl acetate=2:1) show thereaction was complete. Methanol was removed under reduced pressure. Theresidue was washed with ethyl acetate and filtered. The filtrate wasconcentrated to give9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(20 mg, yield: 13%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ:□4.33-4.35 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 4.74-4.76 (d, J=8.0 Hz, 1H),7.08-7.10 (d, J=8.0 Hz, 2H), 7.18-7.24 (m, 6H), 7.27-7.29 (d, J=6.8 Hz,2H), 7.54-7.56 (d, J=7.6 Hz, 1H), 7.62-7.66 (t, J=8.0 Hz, 1H); LC-MS(ESI) m/z: 370 (M+1)⁺.

Example 139-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand8,9-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 13A tert-Butyl 4-isobutyrylpiperazine-1-carboxylate

To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrousdichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol),1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75mmol). After the addition, the mixture was stirred at room temperaturefor 40 mins. The mixture was then cooled to 0° C., compound 1 (13.97 g,75 mmol) was added portionwise. After the addition, the mixture wasstirred at room temperature overnight. The mixture was diluted withdichloromethane (200 mL), washed with saturated sodium bicarbonate (150mL×2), 10% citric acid (150 mL), brine (100 mL), dried over anhydroussodium sulfate, and concentrated to give tert-butyl4-isobutyrylpiperazine-1-carboxylate (15 g, yield: 78%) as a whitesolid. LC-MS (ESI) m/z: 257 (M+1)⁺.

Example 13B 2-Methyl-1-(piperazin-1-yl)propan-1-one

To a stirred mixture of tert-butyl 4-isobutyrylpiperazine-1-carboxylate(6.8 g, 26.5 mmol) in methanol (15 mL) was added hydrochloride/methanol(30 mL, 3M)) at 0° C. After the addition, the mixture was allowed tostir at room temperature overnight. The mixture was concentrated to give2-methyl-1-(piperazin-1-yl)propan-1-one (5.5 g, yield: 100%) as anoff-white solid. ¹H-NMR (400 MHz, CDCl₃) □□δ: 3.82 (brs, 1H), 5.19 (s,3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI) m/z: 157 (M+1)⁺.

Example 13C 3-(4-Isobutyrylpiperazine-1-carbonyl)benzaldehyde

To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrousdichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol),1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.5mmol). After the addition, the mixture was stirred at room temperaturefor 40 mins. Then the mixture was cooled to 0° C., and2-methyl-1-(piperazin-1-yl)propan-1-one (1.06 g, 5.5 mmol) was addedportionwise. After the addition, the mixture was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (50mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citric acid(50 mL), brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde(1.44 g, yield: 95%) as a gum. LC-MS (ESI) m/z: 289 (M+1)⁺.

Example 13D Methyl3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand methyl2,3-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (288 mg,1 mmol) and 4-(benzylideneamino) isobenzofuran-1(3H)-one (237 mg, 1mmol) in ethyl propionate (7.5 mL) was cooled to 0° C. Then a solutionof sodium methoxide in methanol [sodium (92 mg, 4 mmol) in methanol (7.5mL)] was added dropwise. After the addition, the mixture was stirred at25° C. for 18 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give methyl3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(110 mg, yield 20%) and methyl2,3-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(90 mg, yield 12%) as light yellow solids. LC-MS (ESI) m/z: 540 (M+1)⁺and 722 (M+1)⁺.

Example 13E9-(3-(4-Isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(110 mg, 0.20 mmol) in hydrazine monohydrate (5 mL) and methanol (2 mL)was stirred at 25° C. for 4 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give crudeproduct. The crude product was purified by prep-HPLC to give9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(12 mg, yield: 11%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ:□0.96-0.98 (d, J=6.8 Hz, 6H), 2.68-2.95 (m, 2H), 3.28-3.55 (m, 7H),4.19-4.22 (d, J=10.0 Hz, 1H), 4.54-4.57 (d, J=10.4 Hz, 1H), 7.03-7.20(m, 10H), 7.40-7.50 (m, 2H); LC-MS (ESI) m/z: 522 (M+1)⁺.

Example 13F8,9-Bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2,3-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(90 mg, 0.12 mmol) in hydrazine monohydrate (5 mL) and methanol (2 mL)was stirred at 25° C. for 4 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give crudeproduct. The crude product was purified by prep-HPLC to give8,9-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(3.2 mg, yield: 4%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ:□0.95-0.97 (q, 12H), 2.80-2.88 (m, 2H), 2.98-3.08 (m, 3H), 3.33-3.53 (m,13H), 4.23-4.26 (d, J=10.4 Hz, 1H), 4.62-4.64 (d, J=10.0 Hz, 1H),7.02-7.46 (m, 11H); LC-MS (ESI) m/z: 704 (M+1)⁺.

Example 149-(Piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A suspension of8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, 0.35 mmol) and platinum (IV) oxide (60 mg) in methanol (20 mL)was purged in 20 atm hydrogen and stirred at 50° C. for 24 hr. Themixture was filtered and the filtrate was concentrated to give the crudeproduct. The crude product was purified by prep-HPLC to give9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(4 mg, yield: 4%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ□1.19-1.32 (m, 2H), 1.60-1.65 (m, 2H), 1.94-1.97 (d, J=10.0 Hz, 1H),2.31-2.43 (m, 2H), 2.82-2.85 (d, J=12.4 Hz, 1H), 3.02-3.05 (d, J=12 Hz,1H), 3.29-3.32 (dd, J₁=2.8 Hz, J₂=8.4 Hz, 1H), 4.25-4.26 (d, J=2.8 Hz,1H), 7.02-7.05 (dd, J₁=0.8 Hz, J₂=8.8 Hz, 1H), 7.22-7.25 (m, 1H),7.40-7.53 (m, 3H), 8.25-8.29 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)⁺.

Example 159-(Piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, 0.35 mmol), platinum (IV) oxide (60 mg) and concentratehydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at 50° C.under 20 atm of hydrogen. The mixture was filtered out and the filtratewas concentrated to give crude product. The crude product was purifiedby prep-HPLC to give9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(17.6 mg, yield: 16%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ□1.25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.60-1.70 (m, 1H), 1.75-1.84 (m,1H), 1.89-1.98 (m, 1H), 2.50-2.57 (m, 1H), 2.60-2.66 (m, 1H), 3.09-3.21(m, 2H), 3.34-3.37 (dd, J₁=8 Hz, J₂=2.4 Hz, 1H), 4.24 (d, J=2 Hz, 1H),7.02-7.04 (dd, J₁=8 Hz, J₂=0.8 Hz, 1H), 7.09-7.11 (dd, J₁=4.8 Hz, J₂=1.2Hz, 2H), 7.41-7.43 (dd, J₁=7.6 Hz, J₂=0.8 Hz, 1H), 7.50-7.54 (t, J=8 Hz,1H), 8.30-8.32 (dd, J₁=4.4 Hz, J₂=1.6 Hz, 2H); LC-MS (ESI) m/z: 348(M+1)⁺.

Example 168,9-Bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 16A 1-(4-(Diethoxymethyl)phenyl)-N,N,-dimethylmethanamine

A mixture of 1-(4-(diethoxymethyl)benzaldehyde (2.08 g, 10 mmol) anddimethylamine (33% aqueous solution, 2.74 g, 20 mmol) in methanol (20mL) was stirred at room temperature for 40 mins. The mixture was cooledto 0° C., sodium borohydride (0.57 g, 15 mmol) was added portionwise.After the addition, the mixture was stirred at room temperature for 4hr. Methanol was removed under reduced pressure. The residue waspartitioned between water (50 mL) and ethyl acetate (50 mL). The organiclayer was separated. The aqueous layer was extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give1-(4-(diethoxymethyl)phenyl)-N,N,-dimethylmethanamine (1.8 g) as a lightyellow oil which was used in the next step without further purification.MS (ESI) m/z: 237 (M+1)⁺.

Example 16B 4-((Dimethylamino)methyl)benzaldehyde

To a solution of 1-(4-(diethoxymethyl)phenyl)-N,N,-dimethylmethanamine(1.0 g, 4 mmol) in methanol (5 mL), a hydrochloric acid methanolsolution (10 mL) was added dropwise at 0° C. The reaction solution wasstirred at room temperature overnight. Then methanol was removed invacuo to give 4-((dimethylamino)methyl)benzaldehyde (0.68 g, yield 99%)as a light yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 2.26 (s, 6H), 3.50 (s,2H), 7.49 (d, J=6.4 Hz, 2H), 7.84 (d, J=6.4 Hz 2H), 10 (s, 1H). LC-MS(ESI) m/z: 164 (M+1)⁺.

Example 16C Methyl2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-Bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-((dimethylamino)methyl)benzaldehyde (539 mg, 3.3 mmol)and 4-aminoisobenzofuran-1(3H)-one (223 mg, 1.5 mmol) in ethylpropionate (14 mL) was cooled to 0° C. A solution of sodium methoxide inmethanol [sodium (138 mg, 6 mmol) in methanol (4 mL)] was then addeddropwise. After the addition, the mixture was stirred at roomtemperature for 20 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 10:1)to give a mixture of methyl2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(165 mg) as a light yellow solid.

Example 16D8,9-Bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(165 mg, 0.34 mmol) in hydrazine monohydrate (12 mL) and methanol (5 mL)was stirred at 40° C. for 6 hrs. The mixture was filtered to give crudeproduct. The crude product was purified by prep-HPLC to give8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(33.7 mg, yield: 22%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD)δ: □2.04 (s, 6H), 2.05 (s, 6H), 3.19-3.20 (m, 2H), 3.24-3.26 (m, 2H),4.09-4.11 (d, J=8.8 Hz, 1H), 4.52-4.54 (d, J=8.8 Hz, 1H), 6.88-6.90 (m,2H), 6.99-7.07 (m, 7H), 7.42-7.46 (m, 2H). LC-MS (ESI) m/z: 454 (M+1)⁺.

Example 179-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 17A tert-Butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate

A mixture of compound tert-butyl piperazine-1carboxylate (3.725 g, 20mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrousdichloromethane (30 mL) was cooled to 0° C., cyclopropanecarbonylchloride (2.30 g, 22 mmol) was then added dropwise. After the addition,the mixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane (100 mL), washed with 10% citric acid (50mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL),dried over anhydrous sodium sulfate, and concentrated to give tert-butyl4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73%) as awhite solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 0.76-0.81 (m, 2H),0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H),3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255 (M+1)⁺.

Example 17B Cyclopropyl(piperazin-1-yl)methanone Hydrochloride

To a stirred mixture of compound tert-butyl4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, 14.5 mmol) inmethanol (15 mL) was added hydrochloride/methanol (15 mL, 3M)) at 0° C.After the addition, the mixture was allowed to stir at room temperatureovernight. The mixture was concentrated to givecyclopropyl(piperazin-1-yl)methanone hydrochloride (2.74 g, yield 100%)as an off-white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.71-0.76 (m,4H), 1.96-2.03 (m, 1H), 3.04-3.16 (m, 4H), 3.69-4.08 (m, 4H), 9.58 (s,2H); LC-MS (ESI) m/z: 155 (M+1)⁺.

Example 17C4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde

To a stirred mixture of 4-formylbenzoic acid (900 mg, 6 mmol) inanhydrous dichloromethane (30 mL) was added triethylamine (1.52 mg, 15mmol), 1-hydroxybenzotriazole (891 mg, 6.6 mmol), followed by1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (1.254 g,6.6 mmol). After the addition, the mixture was stirred at roomtemperature for 40 mins. Then the mixture was cooled to 0° C. andcyclopropyl(piperazin-1-yl)methanone hydrochloride (1.259 g, 6.6 mmol)was added in portion-wise. After the addition, the mixture was allowedto stir at room temperature overnight. The mixture was diluted withdichloromethane (50 mL), washed with saturated citric acid (100 mL×2),followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL),dried over anhydrous sodium sulfate, and concentrated to give4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg,yield 80%) as a light yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ (ppm):0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.72-1.80 (m, 1H), 3.41-3.81 (m,8H), 7.58-7.60 (d, J=8.0 Hz, 1H), 7.95-7.97 (d, J=8.0 Hz, 1H), 10.07 (s,1H); LC-MS (ESI) m/z: 287 (M+1)⁺.

Example 17D4-(4-(Diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of 4-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol)and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrousdichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24g, 15 mmol) at 0° C. After the addition, the mixture was stirred at roomtemperature for 6 days. The mixture was filtered and the cake was washedwith dichloromethane (50 mL×3). The filtrate was concentrated to givecrude product. The crude product was washed with petroleum ether to give4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (4.3 g,yield 84%) as a light yellow solid. LC-MS (ESI) m/z: 340 (M+1)⁺.

Example 17E Methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (859 mg, 3mmol) and 4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one(1.018 g, 3 mmol) in ethyl propionate (40 mL) was cooled to 0° C. Then asolution of sodium methoxide in methanol [sodium (276 mg, 12 mmol) inmethanol (8 mL)] was added dropwise. After the addition, the mixture wasstirred at room temperature for 20 hr. The mixture was quenched withwater (10 mL) and solvent was removed in vacuum. The residue wasdissolved in water, and then extracted with ethyl acetate (100 mL×4).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated to give crude product. The crudeproduct was purified by chromatography (silica gel, petroleumether/ethyl acetate=10:1 to 1:10) to give methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(500 mg, yield 26%). LC-MS (ESI) m/z: 640 (M+1)⁺.

Example 17F9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(526 mg, 0.82 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3mL) was stirred at 25° C. for 2 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(330 mg, yield 65%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm): 0.72-0.76 (m, 4H), 1.09-1.12 (m, 6H), 1.99 (s, 1H), 3.39-3.73 (m,12H), 4.70 (s, 1H), 5.40 (s, 1H), 5.99 (s, 1H), 6.68-7.31 (m, 9H),7.41-7.61 (m, 3H), 12.19 (s, 1H); LC-MS (ESI) m/z: 622 (M+1)⁺.

Example 17G4-(9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

A mixture of9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(280 mg, 0.45 mmol) in 3N hydrochloric acid (10 mL) was stirred at roomtemperature for 3 hr. Then the mixture was neutralized with potassiumcarbonate. The resulting suspension was filtered to give4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(220 mg, yield 89%) as a light yellow solid. LC-MS (ESI) m/z: 548(M+1)⁺.

Example 17H9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.15 mmol) and 27% methylamine alcohol solution (50 mg, 0.44mmol) in methanol (10 mL) was stirred at room temperature for 40 min.Then the mixture was cooled to 0° C. Sodium borohydride (8.3 mg, 0.23mmol) was added. After the addition, the mixture was stirred at thistemperature for 2 hr. Methanol was removed under reduced pressure. Theresidue was washed with ethyl acetate/methanol (10/1) and filtered. Thefiltrate was concentrated to give the crude product. The crude productwas purified by prep-HPLC to give9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(6.4 mg, yield 7%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 0.83-0.91 (m, 4H), 1.94-2.03 (m, 1H), 2.66-2.68 (d, J=6.0 Hz,3H), 3.35-3.79 (m, 8H), 4.11 (s, 2H), 4.42-4.44 (d, J=7.6 Hz, 1H),4.88-4.90 (d, J=7.2 Hz, 1H), 7.21-7.26 (m, 3H), 7.29-7.36 (m, 4H),7.41-7.43 (d, J=8.4 Hz, 2H), 7.55-7.57 (d, J=7.2 Hz, 1H), 7.63-7.67 (t,J=8.0 Hz, 1H); LC-MS (ESI) m/z: 563 (M+1)⁺.

Example 189-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.15 mmol) and 27% dimethylamine solution (62 mg, 0.44 mmol) inmethanol (10 mL) was stirred at room temperature for 40 min. Then themixture was cooled to 0° C. Sodium borohydride (8.3 mg, 0.22 mmol) wasadded. After the addition, the mixture was stirred at this temperaturefor 2 hr. Methanol was removed under reduced pressure. The residue waswashed with ethyl acetate/methanol (10/1) and filtered. The filtrate wasconcentrated to give the crude product. The crude product was purifiedby prep-HPLC to give9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(4.2 mg, yield 5%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 0.73-0.79 (m, 4H), 1.84 (m, 1H), 2.69 (s, 6H), 3.47-3.72 (m, 8H),4.14 (s, 2H), 4.31-4.33 (d, J=8.0 Hz, 1H), 7.12-7.35 (m, 9H), 7.47-7.58(m, 2H); LC-MS (ESI) m/z: 577 (M+1)⁺.

Example 198-(4-(Hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 208-(4-((Dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 19A tert-Butyl 4-isobutyrylpiperazine-1-carboxylate

To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrousdichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol),1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75mmol). After the addition, the mixture was stirred at room temperaturefor 40 mins. Then the mixture was cooled to 0° C., and tert-butylpiperazine-1-carboxylate (13.97 g, 75 mmol) was added portion-wise.After the addition, the mixture was stirred at room temperatureovernight. The mixture was diluted with dichloromethane (200 mL), washedwith saturated sodium bicarbonate (150 mL×2), 10% citric acid (150 mL),brine (100 mL), dried over anhydrous sodium sulfate, and concentrated togive tert-butyl 4-isobutyrylpiperazine-1-carboxylate (15 g, yield 78%)as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.13-1.14 (d, J=6.8Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, 1H), 3.43-3.58 (m, 4H); LC-MS (ESI)m/z: 257 (M+1)⁺.

Example 19B 2-Methyl-1-(piperazin-1-yl)propan-1-one

To a stirred mixture of tert-butyl 4-isobutyrylpiperazine-1-carboxylate(6.8 g, 26.5 mmol) in methanol (15 mL) was added hydrochloride/methanol(30 mL, 3M)) at 0° C. After the addition, the mixture was allowed tostir at room temperature overnight. The mixture was concentrated to give2-methyl-1-(piperazin-1-yl)propan-1-one (5.5 g, yield 100%) as anoff-white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.99-1.00 (d, J=6.4Hz, 6H), 2.84-2.89 (m, 1H), 3.03-3.07 (d, 4H), 3.68-3.74 (d, 4H), 9.58(s, 2H); LC-MS (ESI) m/z: 157 (M+1)⁺.

Example 19C 4-(4-Isobutyrylpiperazine-1-carbonyl)benzaldehyde

To a stirred mixture of 4-formylbenzoic acid (1.5 g, 10 mmol) inanhydrous dichloromethane (30 mL) was added triethylamine (2.52 g, 25mmol), 1-hydroxybenzotriazole (1.5 g, 11 mmol), followed by1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (2.1 g, 11mmol). After the addition, the mixture was stirred at room temperaturefor 40 mins. Then the mixture was cooled to 0° C. and2-methyl-1-(piperazin-1-yl)propan-1-one (2.12 g, 11 mmol) was added inportion-wise. After the addition, the mixture was allowed to stir atroom temperature overnight. The mixture was diluted with dichloromethane(50 mL), washed with saturated citric acid (100 mL×2), followed bysaturated sodium bicarbonate (100 mL×2), brine (50 mL), dried overanhydrous sodium sulfate, and concentrated to give4-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (2 g, yield 70%) as alight yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.15 (d, 6H), 2.80(brs, 1H), 3.39-3.80 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz,1H), 10.07 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)⁺.

Example 19D Methyl2-(4-(diethoxymethyl)phenyl)-3-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (950 mg,3.3 mmol) and (E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (1.018 g, 3 mmol) in ethylpropionate (40 mL) was cooled to 0° C. Then a solution of sodiummethoxide in methanol [sodium (345 mg, 12 mmol) in methanol (8 mL)] wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 24 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give methyl2-(4-(diethoxymethyl)phenyl)-3-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(491 mg, yield 25%).

Example 19E8-(4-(Diethoxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2-(4-(diethoxymethyl)phenyl)-3-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(491 mg, 0.77 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3mL) was stirred at 25° C. for overnight. The mixture was extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to give8-(4-(diethoxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(365 mg, yield 77%) as a yellow solid.

Example 19F4-(9-(4-(4-(Isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

A mixture of8-(4-(diethoxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(365 mg, 0.59 mmol) in 3N hydrochloric acid (10 mL) was stirred at roomtemperature for 3 hr. Then the mixture was neutralized with potassiumcarbonate. The resulting suspension was filtered to give crude. Thecrude product was purified by prep-HPLC to give the4-(9-(4-(4-(isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, yield 28%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 1.11-1.13 (d, J=6.8 Hz, 6H), □ 2.95-3.14 (brs, 1H), 3.38-3.80 (m,8H), 4.37-4.40 (d, J=7.2 Hz, 1H), 4.75-4.77 (d, J=7.6 Hz, 1H), 7.20-7.33(m, 9H), 7.57-7.59 (d, J=7.6 Hz, 1H), 7.60-7.76 (t, J=8.0 Hz, 1H), 9.92(s, 1H); LC-MS (ESI) m/z: 550 (M+1)⁺.

Examples 19G & 208-(4-(Hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one&8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of compound 7 (50 mg, 0.09 mmol) and 33% dimethylamine aqsolution (25 mg, 0.18 mmol) in methanol (10 mL) was stirred at roomtemperature for 40 min. Then the mixture was cooled to 0° C. Sodiumborohydride (5 mg, 0.13 mmol) was added. After the addition, the mixturewas stirred at this temperature for 2 hr. TLC (petroleum ether/ethylacetate=2:1) show the reaction was complete. Methanol was removed underreduced pressure. The residue was washed with ethyl acetate/methanol(10/1) and filtered. The filtrate was concentrated to give the crudeproduct. The crude product was purified by prep-HPLC to give8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(4 mg, yield 9%) and8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(16 mg, yield 36%) as light yellow solids.8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ (ppm): 1.10-1.12 (d, J=6.8 Hz, 6H), 2.80 (s,6H), 2.96-3.00 (brs, 1H), 3.33-3.70 (m, 8H), 4.12 (s, 2H), 4.43-4.44 (d,J=7.6 Hz, 1H), 4.89-4.91 (d, J=7.6 Hz, 1H), 7.22-7.27 (m, 3H), 7.31-7.37(m, 4H), 7.42-7.44 (d, J=8.0 Hz, 2H), 7.56-7.58 (d, J=7.2 Hz, 1H),7.64-7.68 (t, J=8.0 Hz 1H); LC-MS (ESI) m/z: 579 (M+1)⁺.8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ (ppm): 1.10-1.12 (d, J=6.4 Hz, 6H), 2.95 (brs,1H), 3.33-3.81 (m, 8H), 4.39-4.41 (d, J=8.2 Hz, 1H), 4.53 (s, 2H),4.77-4.79 (d, J=7.6 Hz 1H), 7.20-7.30 (m, 9H), 7.55-7.57 (dd, J₁=8.0 Hz,J₂=1.0 Hz, 1H), 7.63-7.67 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 552(M+1)⁺.

Example 219-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 21A (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of benzaldehyde (1.91 g, 18 mmol) and anhydroussodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (100 mL)was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C.After the addition, the mixture was stirred at room temperature for 6days. The mixture was filtered and the cake was washed withdichloromethane (50 mL×3). The filtrate was concentrated to give crudeproduct. The crude product was washed with petroleum ether to give(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (3.38 g, yield 95%) as awhite solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 5.41 (s, 2H), 7.36-7.37(d, J=7.6 Hz, 1H), 7.49-7.59 (m, 4H), 7.77-7.78 (d, J=7.6 Hz, 1H),7.92-7.94 (d, J=8.0 Hz, 2H), 8.55 (s, 1H), LC-MS (ESI) m/z: 238 (M+1)⁺.

Example 21B Methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (429 mg, 1.5 mmol) and(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one ((355.5 mg, 1.5 mmol) inethyl propionate (12 mL) was cooled to 0° C. Then a solution of sodiummethoxide in methanol [sodium (138 mg, 6 mmol) in methanol (12 mL)] wasadded dropwise. After the addition, the mixture was stirred at 25° C.for 18 hr. The mixture was quenched with water (10 mL) and solvent wasremoved in vacuum. The residue was dissolved in water, and thenextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and concentratedto give crude product. The crude product was purified by chromatography(silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(90 mg, yield 11%). LC-MS (ESI) m/z: 538 (M+1)⁺.

Example 21C9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-3(7H)-one

A mixture of methyl3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(90 mg, 0.16 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give crudeproduct. The crude product was purified by prep-HPLC to give9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(18 mg, yield 22%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ (ppm):0.86-0.94 (m, 4H), 2.00 (s, 1H), 3.33-3.82 (m, 8H), 4.41-4.43 (d, J=8.4Hz, 1H), 4.78-4.80 (d, J=8.4 Hz, 1H), 7.21-7.27 (m, 6H), 7.30-7.35 (m,4H), 7.58-7.60 (m, 1H), 7.65-7.69 (t, J=8.0 Hz, 4H); LC-MS (ESI) m/z:520 (M+1)⁺.

Example 229-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 22A Methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (286 mg, 1 mmol) and(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (237 mg, 1 mmol) inethyl propionate (7.5 mL) was cooled to 0° C. Then a solution of sodiummethoxide in methanol [sodium (92 mg, 4 mmol) in methanol (7.5 mL)] wasadded dropwise. After the addition, the mixture was stirred at 25° C.for 18 hr. The mixture was quenched with water (10 mL) and solvent wasremoved in vacuum. The residue was dissolved in water, and thenextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and concentratedto give crude product. The crude product was purified by chromatography(silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(64 mg, yield 12%). LC-MS (ESI) m/z: 538 (M+1)⁺.

Example 22B9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(64 mg, 0.12 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give crudeproduct. The crude product was purified by prep-HPLC to give9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(8 mg, yield 13%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 0.73-0.81 (m, 4H), 1.18-1.19 (m, 1H), 3.20-3.71 (m, 8H),4.23-4.25 (d, J=10.0 Hz, 1H), 4.59-4.61 (d, J=8.4 Hz, 1H), 7.08-7.26 (m,10H), 7.45-7.54 (m, 2H); LC-MS (ESI) m/z: 520 (M+1)⁺.

Example 239-(3-((Dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(45 mg, 0.12 mmol) and 33% dimethylamine solution (50.2 mg, 0.366 mmol)in methanol (5 mL) was stirred at room temperature for 1 h. Then themixture was cooled to 0° C., sodium borohydride (6.95 mg, 0.184 mmol)was added portionwise. After the addition, the mixture was stirred atthis temperature for 2 hr. Methanol was removed under reduced pressure.The residue was purified by prep-HPLC to give9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(21 mg, yield 44%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.59 (s, 3H), 2.75 (s, 3H), 4.11-4.27 (q, 2H), 4.31-4.34 (d,J=10.4 Hz, 1H), 4.68-4.71 (d, J=10.4 Hz, 1H), 7.17-7.30 (m, 9H),7.33-7.37 (t, J=7.6 Hz, 1H), 7.56-7.58 (d, J=7.6 Hz, 1H), 7.60-7.64 (t,J=8.0 Hz, 1H); LC-MS (ESI) m/z: 396 (M+1)⁺.

Example 248-(3-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 24A(E)-4-(3-(Diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of 3-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol)and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrousdichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24g, 15 mmol) at 0° C. After the addition, the mixture was stirred at roomtemperature for 6 days. The mixture was filtered and the cake was washedwith dichloromethane (50 mL×3). The filtrate was concentrated to givecrude product. The crude product was washed with petroleum ether to give(E)-4-(3-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (3.1g, yield 61%) as a white solid. LC-MS (ESI) m/z: 340 (M+1)⁺.

Example 24B Methyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate3(7H)-one

A mixture of(E)-4-(3-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (678mg, 2 mmol) and benzaldehyde (212 mg, 2.2 mmol) in ethyl propionate (20mL) was cooled to 0° C. Then a solution of sodium methoxide in methanol[sodium (183 mg, 8 mmol) in methanol (10 mL)] was added dropwise. Afterthe addition, the mixture was stirred at room temperature for 24 hr. Themixture was quenched with water (10 mL) and solvent was removed invacuum. The residue was dissolved in water, and then extracted withethyl acetate (100 mL×4). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to givecrude product. The crude product was purified by chromatography (silicagel, petroleum ether/ethyl acetate=10:1 to 1:10) to give a mixture ofmethyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(160 mg, yield 17%).

Example 24C8-(3-(Diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(160 mg, 0.36 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3mL) was stirred at 25° C. for overnight. The mixture was extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to give the8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(90 mg, yield 58%) as a yellow solid. LC-MS (ESI) m/z: 442 (M+1)⁺.

Example 24D3-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

A mixture of8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(90 mg, 0.21 mmol) in 3N hydrochloric acid (10 mL) was stirred at roomtemperature for 3 hr. Then the mixture was neutralized with potassiumcarbonate. The resulting suspension was filtered to give3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(40 mg, yield 50%) as a light yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 4.24 (d, J=7.6 Hz, 1H), 4.77 (d, J=7.6 Hz, 1H), 4.85 (brs, 1H),7.01-7.03 (m, 2H), 7.08-7.10 (m, 1H), 7.21-7.24 (m, 3H), 7.37-7.39 (m,2H), 7.61-7.65 (m, 1H), 7.74-7.75 (m, 2H), 7.79-7.81 (m, 1H), 9.59 (brs,1H), 9.92 (s, 1H). LC-MS (ESI) m/z: 368 (M+1)⁺.

Example 24E8-(3-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(40 mg, 0.11 mmol) and 27% methylamine alcohol solution (28 mg, 0.23mmol) in methanol (10 mL) was stirred at room temperature for 40 min.Then the mixture was cooled to 0° C. Sodium borohydride (7 mg, 0.18mmol) was added. After the addition, the mixture was stirred at thistemperature for 2 hr. Methanol was removed under reduced pressure. Theresidue was washed with ethyl acetate/methanol (10/1) and filtered. Thefiltrate was concentrated to give the crude product. The crude productwas purified by prep-HPLC to give8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(4 mg, yield 10%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.44 (s, 6H), 3.99 (m, 2H), 4.21 (m, 1H), 4.69 (m, 1H), 6.98-7.00(d, J=7.2 Hz, 1H), 7.05-7.10 (m, 4H), 7.21-7.23 (m, 3H), 7.31 (s, 1H),7.46-7.48 (d, J=8.0 Hz, 1H), 7.51-7.53 (m, 1H). LC-MS (ESI) m/z: 383(M+1)⁺.

Example 258-(4-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 25A Methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(4-(dimethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (600mg, 1 mmol) and benzaldehyde (616 mg, 3 mmol) in ethyl propionate (20mL), sodium methanolate (414 mg, 7.6 mmol) were added and the mixturewas stirred at room temperature overnight. Then the resulting mixturewas evaporated under reduced pressure and extracted with ethyl acetate(100 mL×4) and concentrated. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1)to obtain a white solid of methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg, yield 22%). LC-MS (ESI) m/z: 432 (M+1)⁺.

Example 25B8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg, 0.28 mmol) and 85% hydrazine monohydrate (20 mL) were added andthe mixture was stirred under 40° C. for 3 h. The resulting mixture wasevaporated under reduced pressure to 10 mL and then filtered to give8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(89 mg, yield 78%). LC-MS (ESI) m/z: 414 (M+1)⁺.

Example 25C4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(89 mg, 0.22 mmol) and 20 ml of 3 N hydrochloric acid were added and themixture was stirred at room temperature for 2 h. The resulting mixturewas neutralized with potassium carbonate and then filtered to give4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(59, yield 73%). LC-MS (ESI) m/z: 368.

Example 25D8-(4-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(59 mg, 0.16 mmol) and dimethylamine (5 mL) were added and the mixturewas stirred at room temperature for 2 h. Then 20 mg of sodiumborohydride was added and stirred for another 2 h. The resulting mixturewas evaporated under reduced pressure and purified by prep-HPLC to give8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(20 mg, yield 32%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.18 (s, 6H),4.28-4.30 (d, J=8 Hz, 1H), 4.72-4.74 (d, J=8 Hz, 1H), 7.06-7.08 (m, 2H),7.13-7.20 (m, 6H), 7.23-7.25 (m, 2H), 7.54-7.65 (m, 2H). LC-MS (ESI)m/z: 397 (M+1)⁺.

Example 26 & 278-(4-(Morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand8-(4-(Hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(59 mg, 0.16 mmol) and morpholine (42 mg) were added and the mixture wasstirred at room temperature for 2 h. Then 20 mg of sodium borohydridewas added and stirred for another 2 h. The resulting mixture wasevaporated under reduced pressure and purified by prep-HPLC to give8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(8 mg, yield 11%) and8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(7 mg, yield 12%).8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.31 (s, 4H), 3.36 (s, 4H), 3.61-3.63(m, 4H), 4.15-4.17 (d, J=10 Hz, 1H), 4.58-4.61 (d, J=10 Hz, 1H), 4.79(s, 1H), 6.94-7.19 (m, 10H), 7.51-7.55 (m, 1H), 7.68-7.70 (m, 1H), 7.63(s, 1H). LC-MS (ESI) m/z: 439 (M+1)⁺.8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.21-4.25 (m, 1H), 4.63-4.70 (m, 1H),4.86 (s, 1H), 6.97-7.06 (m, 3H), 7.11-7.26 (m, 7H), 7.58-7.62 (m, 1H),7.75-7.77 (m, 1H). LC-MS (ESI) m/z: 370 (M+1)⁺.

Examples 28 & 299-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 28A 3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde

To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) inanhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5mmol), 1-hydroxybenzotriazole (466 mg, 3.45 mmol), followed by1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg,3.45 mmol). After the addition, the mixture was stirred at roomtemperature for 40 mins. Then the mixture was cooled to 0° C. andcyclopropyl(piperazin-1-yl)methanone hydrochloride (629 mg, 3.3 mmol)was added in portion-wise. After the addition, the mixture was allowedto stir at room temperature overnight. The mixture was diluted withdichloromethane (50 mL), washed with saturated citric acid (100 mL×2),followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL),dried over anhydrous sodium sulfate, and concentrated to give3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl) benzaldehyde (810 mg,yield 94%) as a light yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ (ppm):0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73-1.76 (m, 1H), 3.47-3.77 (m,8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.70-7.72 (d, J=7.6 Hz, 1H), 7.95-7.98(m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)⁺.

Example 28B Methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (940 mg, 3.3 mmol) and (E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (1.018 g, 3 mmol) in ethylpropionate (40 mL) was cooled to 0° C. Then a solution of sodiummethoxide in methanol [sodium (345 mg, 15 mmol) in methanol (8 mL)] wasadded drop-wise. After the addition, the mixture was stirred at roomtemperature for 24 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(425 mg, yield 22%).

Example 28C9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-(425 mg, 0.67 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3mL) was stirred at 25° C. for overnight. The mixture was extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to give the9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(290 mg, yield 70%) as a yellow solid.

Example 28D4-(9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

A mixture of9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(290 mg, 0.48 mmol) in 3N hydrochloric acid (10 mL) was stirred at roomtemperature overnight. Then the mixture was neutralized with potassiumcarbonate. The resulting suspension was filtered to give crude. Thecrude product was purified by prep-HPLC to give the4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(20 mg, yield 8%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 0.83-0.91 (m, 4H), 1.94-2.03 (m, 1H), 3.18-3.23 (m, 1H),3.46-3.82 (m, 7H), 4.42 (d, J=7.6 Hz, 1H), 4.87 (d, J=7.4 Hz, 1H),7.22-7.41 (m, 7H), 7.52-7.54 (d, J=8.0 Hz, 2H), 7.60 (d, 1H), 9.94 (s,1H); LC-MS (ESI) m/z: 548 (M+1)⁺.

Examples 28E & 29E9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(20 mg, 0.04 mmol) and 33% dimethylamine aq solution (10 mg, 0.07 mmol)in methanol (10 mL) was stirred at room temperature for 40 min. Then themixture was cooled to 0° C. Sodium borohydride (2 mg, 0.06 mmol) wasadded. After the addition, the mixture was stirred at this temperaturefor 2 hr. Methanol was removed under reduced pressure. The residue waswashed with ethyl acetate/methanol (10/1) and filtered. The filtrate wasconcentrated to give the crude product. The crude product was purifiedby prep-HPLC to give the compound9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(4 mg, yield 19%) and9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(2 mg, yield 9%) as light yellow solids.9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.83-0.91 (m, 4H), 1.94-2.03 (m, 1H),2.81 (s, 6H), 3.18-3.23 (m, 1H), 3.35-3.79 (m, 7H), 4.26 (s, 2H), 4.40(d, J=7.6 Hz, 1H), 4.82 (d, J=7.2 Hz, 1H), 7.22-7.29 (m, 4H), 7.31-7.33(m, 1H), 7.37-7.45 (m, 4H), 7.58-7.60 (d, J=8.0 Hz, 1H), 7.64-7.68 (t,J=8.0 Hz, 1H); LC-MS (ESI) m/z: 577 (M+1)⁺.9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ (ppm): 0.83-0.91 (m, 4H), 1.94-2.01 (m, 1H),3.11-3.14 (m, 1H), 3.35-3.79 (m, 7H), 4.37-4.40 (d, J=10.0 Hz, 1H), 4.55(s, 2H), 4.38 (d, J=7.6 Hz, 1H), 4.73-4.76 (d, J=9.6 Hz, 1H), 7.12 (s,1H), 7.20-7.30 (m, 7H), 7.34-7.38 (t, J=8.0 Hz, 1H), 7.56-7.58 (d, J=7.6Hz, 1H), 7.62-7.66 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 550 (M+1)⁺.

Example 309-(4-(4-Isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(40 mg, 0.07 mmol) and 33% dimethylamine aq solution (17 mg, 0.14 mmol)in methanol (10 mL) was stirred at room temperature for 40 min. Then themixture was cooled to 0° C. Sodium borohydride (4 mg, 0.11 mmol) wasadded. After the addition, the mixture was stirred at this temperaturefor 2 hr. Methanol was removed under reduced pressure. The residue waswashed with ethyl acetate/methanol (10/1) and filtered. The filtrate wasconcentrated to give the crude product. The crude product was purifiedby prep-HPLC to give the compound9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(18 mg, yield 49%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 1.10-1.12 (d, J=6.8 Hz, 6H), 2.67 (s, 3H), 2.81 (brs 1H),3.33-3.70 (m, 8H), 4.12 (s, 2H), 4.43-4.75 (d, J=7.6 Hz, 1H), 4.88 (d,J=7.4 Hz, 1H), 7.22-7.27 (m, 3H), 7.31-7.37 (m, 4H), 7.42-7.44 (d, J=8.0Hz, 2H), 7.56-7.58 (d, J=7.2 Hz, 1H), 7.64-7.68 (t, J=8.0 Hz, 1H); LC-MS(ESI) m/z: 579 (M+1)⁺.

Example 319-(3-(4-Isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 31A 3-(4-Isobutyrylpiperazine-1-carbonyl)benzaldehyde

To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrousdichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol),1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1.05 g,5.5 mmol). After the addition, the mixture was stirred at roomtemperature for 40 mins. Then the mixture was cooled to 0° C. and2-methyl-1-(piperazin-1-yl)propan-1-one hydrochloride (1.06 g, 5.5 mmol)was added portionwise. After the addition, the mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(50 mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citricacid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde(1.44 g, yield 95%) as a gum. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.13-1.14(d, J=6.8 Hz 6H), 2.80 (s, 1H), 3.46-3.80 (m, 8H), 7.62-7.66 (t, J=7.6Hz, 1H), 7.69-7.71 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.96-7.99 (dd,J₁=7.6 Hz, J₂=1.2 Hz, 1H), 10.06 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)⁺.

Example 31B (E)-4-(Pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one

A mixture of 4-aminoisobenzofuran-1(3H)-one (894 mg, 6 mmol),isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6g) in anhydrous ethanol (70 mL) was heated to reflux for two days. Themixture was cooled to room temperature and filtered. The filtrate wasconcentrated to give the crude product. The crude product was washedwith petroleum ether to give(E)-4-(pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one (1.1 g, yield77%) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 5.44 (s, 1H),7.40-7.42 (d, J=7.6 Hz, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (d,J=5.6 Hz, 2H), 7.84-7.86 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d,J=4.8 Hz, 1H); LC-MS (ESI) m/z: 239 (M+1)⁺.

Example 31C Methyl 3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (288 mg,1 mmol) and (E)-4-(pyridin-4-ylmethyleneamino)-isobenzofuran-1(3H)-one(238 mg, 1 mmol) in ethyl propionate (7.5 mL) was cooled to 0° C. Then asolution of sodium methoxide in methanol [sodium (92 mg, 4 mmol) inmethanol (7.5 mL)] was added drop-wise. After the addition, the mixturewas stirred at 25° C. for 18 hr. The mixture was quenched with water (10mL) and solvent was removed in vacuum. The residue was dissolved inwater, and then extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated to give crude product. The crude product waspurified by chromatography (silica gel, petroleum ether/ethylacetate=10:1 to 1:10) to give methyl 3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(140 mg, yield 26%). LC-MS (ESI) m/z: 541 (M+1)⁺.

Example 31D9-(3-(4-Isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl 3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(140 mg, 0.26 mmol) in 85% hydrazine monohydrate (10 mL) and methanol (3mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, and concentrated to give crudeproduct. The crude product was purified by prep-HPLC to give compound9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(11 mg, yield 8%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ (ppm):1.11-1.13 (m, 6H), 2.95-2.98 (m, 1H), 3.26-3.68 (m, 8H), 4.40-4.42 (d,J=8.4 Hz, 1H), 4.82-4.84 (d, J=8.4 Hz, 1H), 7.19-7.32 (m, 4H), 7.36-7.39(m, 3H), 7.59-7.68 (m, 2H), 8.41-8.42 (d, J=6.0 Hz, 2H); LC-MS (ESI)m/z: 523 (M+1)⁺.

Following the synthetic strategy outlined in Synthetic Scheme I andSynthetic Scheme II and the appropriate experimental procedure asdescribed in Examples 2 to Example 31 and using different aldehydes 2and appropriate 4-aminoisobenzofuran-1(3H)-one 1, the followingcompounds are made.

Example 329-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 339-(3-((Methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 349-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 359-(3-(Hydroxymethyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 369-(4-((Methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 379-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 389-(3-((Methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 399-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 409-(4-((Methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 419-(3-(Hydroxymethyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 429-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 439-(3-((Methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 449-(3-(Hydroxymethyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 459-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 469-(4-((Methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 479-Phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 489-Phenyl-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 499-Phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 505-Fluoro-9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 519-(3-((Dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 525-Fluoro-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 539-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 545-Fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 559-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 565-Fluoro-9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 579-(3-((Dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 588-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 595-Fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 605-Fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-oneExample 617-Methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A solution of8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (1.04mmol) in methanol (20 mL) is treated with formaldehyde (37 wt % inwater, 270 μL, 3.61 mmol) at room temperature for overnight. Sodiumcyanoborohydride (228 mg, 3.61 mmol) is added and the solution isstirred at room temperature for 3 h. After concentration under reducedpressure, the residue is dissolved in a mixture of trifluoroacetic acidand water and is purified by HPLC giving the7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onein good yield.

Example 627-Ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Following the experimental conditions outlined in Example 61, replacingthe formaldehyde with acetaldehyde, the title compound7-ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneis made.

Example 635-Fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 63A Methyl 5-fluoro-2-methyl-3-nitrobenzoate

To a solution of conc. H₂SO₄ (700 mL) was added portion-wise5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then amixture of conc. HNO₃ (60.4 g, 624 mmol) in conc. H₂SO₄ (60 mL) wasadded drop-wise at −5˜0° C. in a period of about 1.5 hrs. After theaddition, the mixture was stirred at this temperature for 2 hrs. TLC(petroleum ether/EtOAc=1:1) showed the reaction was complete. Themixture was poured into crash ice with vigorous stirring and theprecipitate was collected by filtration. The precipitate was dissolvedin EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentratedto give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solutionof this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in drymethanol (500 mL) was cooled to 0° C., SOCl₂ (64.52 g, 542.3 mmol) wasadded drop-wise. After the addition, the mixture was heated to refluxfor 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction wascomplete. Solvent was removed under reduced pressure to give crudeproduct. The crude product was purified by silica gel chromatography(petroleum ether to petroleum ether/EtOAc=50:1) to give methyl5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as awhite solid. ¹H-NMR (400 MHz, CDCl₃) □□δ (ppm): 2.59 (s, 3H), 3.95 (s,3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214(M+1)⁺, 216 (M+3)⁺.

Example 63B 6-Fluoro-4-nitroisobenzofuran-1(3H)-one

A mixture of methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, 130.5mmol), NBS (27.8 g, 156.6 mmol) and BPO (3.13 g, 13.1 mmol) in CCl₄ (400mL) was heated to reflux overnight. TLC (petroleum ether/EtOAc=15:1)showed the starting material was consumed completely. Water (200 mL) wasadded and CCl₄ was removed under reduced pressure. The residue wasextracted with DCM (200 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give crude methyl2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, yield 94%) as abrown oil. A mixture of methyl2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, 123 mmol) in 1,4-dioxane (250 mL) and water (62.5 mL) was heated to reflux for 4 days.TLC (petroleum ether/EtOAc=15:1) showed the starting material wasconsumed completely. Dioxane was removed under reduced pressure. Theresidue was extracted with EtOAc (300 mL×4). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated to give crudeproduct. The crude product was purified by gel chromatography (petroleumether to petroleum ether/EtOAc=5:1) to give6-fluoro-4-nitroisobenzofuran-1(3H)-one (19.2 g, yield 79%) as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) □□δ (ppm): 5.74 (s, 2H), 7.97-7.98 (dd,1H), 8.24-8.27 (dd, 1H); LC-MS (ESI) m/z: 198 (M+1)⁺.

Example 63C 4-Amino-6-fluoroisobenzofuran-1(3H)-one

A suspension of 6-fluoro-4-nitroisobenzofuran-1(3H)-one (9.6 g, 48.7mmol) and Pd/C (10%, 1 g) in EtOAc (300 mL) was stirred at 25° C. under1 atmosphere of hydrogen for 12 hr. TLC (petroleum ether/EtOAc=2:1)showed the reaction was complete. The mixture was filtered, and the cakewas washed with EtOAc (100 mL×3). The filtrate was concentrated to give4-amino-6-fluoroisobenzofuran-1(3H)-one (7.5 g, yield 92%) as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) □□ δ (ppm): 3.85 (br s, 2H), 5.14-5.15(d, 2H), 6.62-6.65 (dd, 1H), 6.98-7.00 (dd, 1H); LC-MS (ESI) m/z: 168(M+1)⁺.

Example 63D (E)-4-(Benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one

To a stirred mixture of benzaldehyde (4.125 g, 29.9 mmol) and anhydrousmagnesium sulfate (36 g, 299 mmol) in anhydrous acetonitrile (200 mL)was added 4-amino-6-fluoroisobenzofuran-1(3H)-one (5 g, 29.9 mmol) at 0°C. After the addition, the mixture was stirred at room temperature for 6days. The mixture was filtered and the cake was washed with ethylacetate (50 mL×3). The filtrate was concentrated to give crude product.The crude product was washed with petroleum ether to give(E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (5 g, yield:66%). ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 5.40 (s, 2); 7.11-7.14 (dd, 1H),7.44-7.46 (dd, 2H), 7.53-7.59 (m, 3H), 7.93-7.95 (m, 2H), 8.54 (s, 1H);LC-MS (ESI) m/z: 256 (M+1)⁺.

Example 63E Ethyl7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (2g, 7.8 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (0.949 g, 8.63mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol [sodium (722 mg, 31.37 mmol) in ethanol (30mL)] was added drop-wise. After the addition, the mixture was stirred atroom temperature for 2 hr. The mixture was quenched with water (10 mL)and solvent was removed in vacuum. The residue was dissolved in water,and then extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give the ethyl7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(141 mg). ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 1.18-1.22 (t, 3H), 3.31(s, 3H), 4.17-4.21 (q, 2H), 4.621-4.65 (d, 2H), 5.17-5.20 (d, 1H),6.48-6.51 (dd, 1H), 6.70-6.73 (m, 2H), 6.86 (s, 1H), 7.24-7.30 (m, 3H),7.42-7.44 (t, 2H), 7.76 (s, 1H); LC-MS (ESI) m/z: 394 (M+1)⁺.

Example 63F5-Fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(141 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) wasstirred at 45° C. for overnight. Methanol was removed under reducedpressure. The mixture was filtered and washed with water to give5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(11 mg, yield: 9%). ¹H-NMR (400 MHz, CD₃OD) □□δ (ppm): 3.34 (s, 3H),4.65 (d, J=8.0 Hz, 1H), 4.94 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.88-7.02(m, 2H), 7.18 (dd, 1H), 7.28-7.29 (m, 3H), 7.34-7.36 (m, 2H); ¹⁹F-NMR(400 MHz, CD₃OD) δ: −105.70 (s); LC-MS (ESI) m/z: 362 (M+1)⁺.

Example 645-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 64A(E)-6-Fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one

4-amino-6-fluoroisobenzofuran-1(3H)-one (1.5 g, 8.98 mmol),4-fluorobenzaldehyde (1.67 g, 13.47 mmol) and 12.75 g of MgSO₄ wereadded into 40 ml of DCM and stirred under reflux overnight, then themixture was evaporated under reduced pressure and the residues was driedin vacuum. 850 mg of(E)-6-fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one wasobtained. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 5.37 (s, 2); 7.09-7.12 (dd,1H), 7.19-7.23 (t, 2H), 7.43-7.45 (dd, 1H), 7.92-7.95 (m, 2H), 8.49 (s,1H); LC-MS (ESI) m/z: 274 (M+1)⁺.

Example 64B Methyl7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

(E)-6-Fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (850mg, 3.13 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (342 mg, 3.13mmol), sodium methanolate (851 mg, 12.52 mmol) and ethyl propionate (50ml) were added and the mixture was stirred at room temperatureovernight. Then the resulting mixture was evaporated under reducedpressure and extracted with EtOAc (4×100 ml) and concentrated. The crudeproduct was purified by column chromatography (silica gel, petroleumether:EtOAc 20:1 to 5:1). 20 mg of methyl7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylatewas obtained. LC-MS (ESI) m/z: 412 (M+1)⁺.

Example 64C5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(20 mg, 0.048 mmol) and hydrazine (3 ml) were added MeOH (20 ml) and themixture was stirred room temperature for 3 h. The resulting mixture wasevaporated under reduced pressure to 5 ml and then filtered; 5.6 mg of5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas obtained. ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 3.35 (s, 3H), 4.65 (d,1H), 4.95 (d, 1H), 6.84 (s, 1H), 6.87-6.91 (m, 2H), 7.02 (t, 2H),7.17-7.20 (m, 1H), 7.37-7.40 (m, 1H). LC-MS (ESI) m/z: 380 (M+1)⁺.

Example 658-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 65A Ethyl2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (678mg, 2 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (242 mg, 2.2 mmol),sodium ethanolate (544 mg, 8.0 mmol), and ethyl propionate (50 ml) wasstirred at room temperature for 3 hr. Then the resulting mixture wasevaporated under reduced pressure and extracted with ethyl acetate (100mL×4) and concentrated. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate=20:1 to 1.5:1)to give ethyl2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateas solid (50 mg, yield 5%). LC-MS (ESI) m/z: 478 (M+1)⁺.

Example 65B8-(4-(Diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(490 mg, 1.03 mmol), methanol (20 mL) and hydrazine monohydrate (2 mL)was stirred under 25° C. for 3 hr. The resulting mixture was evaporatedunder reduced pressure to 10 ml and then filtered, 250 mg of8-(4-(diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a solid was obtained, yield 55%. LC-MS (ESI) m/z: 446 (M+1)⁺.

Example 65C4-(9-(1-Methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

A mixture of8-(4-(Diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(50 mg, 0.11 mmol) and 2 ml of hydrochloric acid (3 N) was stirred atroom temperature for 2 hr. The reaction mixture was neutralized by K₂CO₃to pH=7 and then filtered, 29 mg of4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehydewas obtained, yield 70%. LC-MS (ESI) m/z: 372 (M+1)⁺.

Example 65D8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.22 mmol), acetic acid (60 uL) and 27% dimethylamine alcoholsolution (2.5 mL, 15 mmol) in acetonitrile (7 mL) was stirred at roomtemperature for 4h. Then the mixture was cooled to 0° C. NaBH₃CN (36 mg,0.67 mmol) was added. After the addition, the mixture was stirred atroom temperature for 4 hr. Methanol was removed under reduced pressure.The residue was washed with ethyl acetate and filtered. The filtrate wasconcentrated to give8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(30 mg, yield 34%) as a white solid. ¹H-NMR: (400 MHz, DMSO-d₆) δ (ppm):2.11 (s, 6H), 3.36 (s, 2H), 3.37 (s, 3H), 4.65 (d, J=10.4 Hz, 1H), 4.92(d, J=10.4 Hz, 1H), 6.76 (s, 1H), 6.89 (s, 1H), 7.20 (d, J=7.6 Hz, 3H),7.35 (d, J=8.0 Hz, 2H), 7.43 (d, J=6.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H);LC-MS (ESI) m/z: 401 (M+1)⁺.

Example 669-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 66A Ethyl3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 1H-imidazole-5-carbaldehyde (800 mg, 8.3 mmol),2-iodopropane (1.7 g, 10 mmol) and potassium carbonate (1.4 g) in DMF(30 mL) was heated to 50° C. overnight. The mixture was evaporated underreduced pressure, and then extracted with ethyl acetate (100 mL×4). Thecombined organic layers were dried over anhydrous sodium sulfate,concentrated to give 1-isopropyl-1H-imidazole-5-carbaldehyde (1.1 g),LC-MS (ESI) m/z: 139 (M+1)⁺. This compound (1.1 g, 8.0 mmol) and(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (1.7 g, 7.2 mmol) wereadded in ethyl propionate (50 mL) then sodium ethoxide was added under0° C. The mixture was stirred overnight at room temperature. The mixturewas concentrated and the residue was extracted with ethyl acetate (100mL×4). The organic layer dried over anhydrous sodium sulfate, purifiedby chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to1:1) to give ethyl3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(770 mg, yield 30%). LC-MS (ESI) m/z: 404 (M+1)⁺.

Example 66B9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A suspension of ethyl3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(770 mg, 1.9 mmol) and hydrazine monohydrate (6 ml, 85%) were added inmethanol (10 mL) and stirred at 50° C. overnight. The mixture wasfiltered, and the white solid was washed with methanol and dried to give9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(90 mg, yield 13%). ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 0.82-0.84 (d,J=6.8 Hz, 3H), 1.27-1.29 (d, J=6.4 Hz, 3H), 3.30-3.33 (t, J=6.6 Hz, 1H),4.67-4.70 (d, J=11.2 Hz, 1H), 4.92-4.95 (d, J=11.2 Hz, 1H), 6.80 (s,1H), 7.01 (s, 1H), 7.16-7.18 (s, 1H), 7.24-7.28 (m, 3H), 7.31 (s, 1H),7.36-7.39 (m, 3H), 7.55-7.59 (m, 1H); LC-MS (ESI) m/z: 372 (M+1)⁺.

Example 679-(4-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 67A 1-Benzyl-4-methyl-1H-imidazole-2-carbaldehyde

To a solution of 4-methyl-1H-imidazole (1 g, 5.8 mmol) in 6 mL THFcooled to −50° C. was added n-BuLi (2.9 mL, 625 mmol). The mixture wasstirred at −50° C. 40° C. for 2h. Then cooled to −78° C. and added inDMF (0.87 mL) drop-wise. After addition the ice bath was removed, andthe mixture was stirred at room temperature 30 min. The resultingmixture was evaporated under reduced pressure to 10 mL and thenfiltered; the crude product was purified by column chromatography toobtain 1-benzyl-4-methyl-1H-imidazole-2-carbaldehyde (450 mg, yield38%). LC-MS (ESI) m/z: 201 (M+1)⁺.

Example 67B Methyl3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 1-benzyl-4-methyl-1H-imidazole-2-carbaldehyde (450 mg, 2.25mmol), (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (640 mg, 2.7mmol), sodium methanolate (207 mg, 9 mmol) and ethyl propionate (25 mL)were stirred at room temperature overnight. Then the resulting mixturewas evaporated under reduced pressure and extracted with ethyl acetate(4×100 mL) and concentrated to give methyl3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(250 mg, yield 25%). LC-MS (ESI) m/z: 438 (M+1)⁺.

Example 67C9-(1-Benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(250 mg, 0.57 mmol) and hydrazine monohydrate (3 mL) was stirred roomtemperature for 5 h. The resulting mixture was evaporated under reducedpressure to 15 ml and then filtered; the filtrate was concentrated togive9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a white solid (40 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)⁺.

Example 67D9-(4-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(40 mg, 0.09 mmol) and palladium hydroxide on carbon catalyst (40 mg,20% wt) in anhydrous methanol (15 mL) was purged with hydrogen (1 bar)at room temperature for 12 hr. The mixture was filtered and the filtratewas concentrated to give crude product, which was purified by pre-HPLCto give9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(27 mg, yield 87%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.22 (dd, 3H),4.77-4.86 (m, 2H), 7.06 (s, 1H), 7.20 (d, 1H), 7.36 (t, 5H), 7.55 (d,1H), 7.62 (t, 1H); LC-MS (ESI) m/z: 344 (M+1)⁺.

Example 688-Phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 68A Methyl4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of thiazole-5-carbaldehyde (500 mg, 4 mmol),(E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (960 mg, 4 mmol), sodiummethanolate (375 mg, 16.1 mmol) and ethyl propionate (30 mL) werestirred at room temperature overnight. Then the resulting mixture wasevaporated under reduced pressure and extracted with ethyl acetate(4×100 mL) and concentrated. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate 10:1 to 1:1)to give methyl4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(110 mg, yield 7%). LC-MS (ESI) m/z: 379 (M+1)⁺.

Example 68B8-Phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(110 mg, 0.29 mmol) and hydrazine monohydrate (2 mL) were added tomethanol (10 mL) and the mixture was stirred room temperature for 4 h.The resulting mixture was evaporated under reduced pressure to 10 mL andthen filtered; the filtrate was concentrated to give8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(13 mg, yield 13%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ (ppm):4.67 (d, 1H), 4.78 (d, 1H), 7.10-7.19 (m, 4H), 7.24 (t, 2H), 7.45-7.56(m, 2H), 8.76 (s, 1H); LC-MS (ESI) m/z: 347 (M+1)⁺.

Example 699-(Furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 69A Ethyl3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (948 mg, 4mmol) and furan-3-carbaldehyde (422 mg, 4.4 mmol) in ethyl propionate(30 mL) was cooled to 0° C. Then a solution of sodium ethanoxide inethanol [sodium (368 mg, 16 mmol) in ethanol (20 mL)] was addeddropwise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1)to give ethyl3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(80 mg, yield: 5%). LC-MS (ESI) m/z: 362 (M+1)⁺.

Example 69B9-(Furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(80 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) wasstirred at 45° C. overnight. Methanol was removed under reducedpressure. The crude product was purified by prep-HPLC to give9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(5 mg, yield 7%). ¹H-NMR (400 MHz, CD₃OD) □□ δ (ppm): 4.19 (d, J=8.0 Hz,1H), 4.67 (d, J=8.0 Hz, 1H), 6.26 (s, 1H), 7.07-7.21 (m, 7H), 7.30 (s,1H), 7.27 (m, 1H), 7.41 (d, 1H), 7.51 (m, 1H); LC-MS (ESI) m/z: 330(M+1)⁺.

Example 708-(4-((4-Ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (1mL) followed by the addition of 1-ethylpiperazine (121 mg, 1.63 mmol).After the addition, the mixture was stirred at room temperatureovernight. Then the mixture was cooled to 0° C. NaBH (OAc)₃ (173 mg,0.81 mmol) was added. After the addition, the mixture was stirred atthis temperature for 12 hr. dichloromethane was removed under reducedpressure. The residue was washed with ethyl acetate/methanol (10/1) andfiltered. The filtrate was concentrated to give the crude product. Thecrude product was purified by prep-HPLC to give8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(135 mg, yield 47%) as white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.74-3.11 (m, 8H), 4.01-4.10 (m, 3H),4.33 (dd, 1H), 4.78 (dd, 1H), 7.13-7.31 (m, 10H), 7.37 (d, 1H), 7.47 (s,1H), 7.58 (t, 3H); LC-MS (ESI) m/z: 452 (M+1)⁺.

Example 719-Phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A solution of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid(196 mg, 3.24 mmol) and tert-butyl piperazine-1-carboxylate (304 mg,1.63 mmol) at room temperature and stirred overnight. Then NaBH (OAc)₃(173 mg, 0.81 mmol) was added to the mixture at 0° C., stirred for oneday. The reaction mixture was quenched with aqueous sodium bicarbonate,extracted with dichloromethane. The combined organic layer was washed bybrine, dried over anhydrous sodium sulfate, concentrated to give thecrude product which was purified by flash chromatography to obtain asolution. To the solution obtained (concentrated to about 50 mL) wasadded conc. HCl (10 mL) at room temperature and stirred overnight. Themixture was extracted with ethyl acetate for three times, the aqueousphase was concentrated to give9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(127 mg, yield 46%). ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 3.47 (br s, 7H),3.60 (m, 1H), 4.32 (s, 2H), 4.38 (d, 1H), 4.83 (d, 1H), 5.41 (br s, 2H),7.19 (m, 6H), 7.24 (m, 3H), 7.55 (m, 4H), 9.87 (br s, 2H), 12.20 (s,1H); LC-MS (ESI) m/z: 438 (M+1)⁺.

Example 728-(1-Methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 72A(E)-4-((l-Methyl-1H-imidazol-2-yl)methyleneamino)benzofuran-1(3H)-one

To a stirred mixture of 1-methyl-1H-imidazole-2-carbaldehyde (2.5 g, 23mmol) and anhydrous sodium sulfate (26.9 g, 190 mmol) in anhydrousdichloromethane (500 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.8g, 19 mmol) at 0° C. After the addition, the mixture was stirred at roomtemperature for 6 days. The mixture was filtered and the cake was washedwith dichloromethane (50 mL×3). The filtrate was concentrated to givecrude product. The crude product was washed with petroleum ether to give(E)-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)benzofuran-1(3H)-one (5g, yield 98%) as a white solid. LC-MS (ESI) m/z: 242 (M+1)⁺.

Example 72B Methyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-((l-methyl-1H-imidazol-2-yl)methyleneamino)benzofuran-1(3H)-one(241 mg, 1 mmol) and benzaldehyde (116 mg, 1.1 mmol) in ethyl propionate(10 mL) was cooled to 0° C. Then a solution of sodium methoxide inmethanol [sodium (92 mg, 4 mmol) in methanol (5 mL)] was addeddrop-wise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give a crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give a mixture of methyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(87 mg, yield: 24%). LC-MS (ESI) m/z: 362 (M+1)⁺, 376 (M+1)⁺.

Example 72C8-(1-Methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(87 mg) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) wasstirred at room temperature for overnight. The mixture was extractedwith ethyl acetate (50 mL×3). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated togive the crude. The crude product was purified by pre-HPLC to give8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(34 mg, yield 42%) as a yellow solid. ¹H-NMR (400 MHz, CD₃OD) □□ δ(ppm): 3.41 (s, 3H), 4.49 (d, 1H), 5.35 (d, 1H), 7.18-7.20 (m, 2H),7.26-7.29 (m, 1H), 7.33-7.35 (m, 3H), 7.40 (d, 1H), 7.61 (d, 1H),7.71-7.75 (m, 2H); LC-MS (ESI) m/z: 344 (M+1)⁺.

Example 739-(1-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 73A Ethyl3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (500 mg,2.1 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (255 mg, 2.3 mmol) inethyl propionate (20 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol [sodium (194 mg, 8.4 mmol) in ethanol (10 mL)] wasadded drop-wise. After the addition, the mixture was stirred at roomtemperature for 2.5 hr. The mixture was quenched with water (20 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andfiltered; the cake was washed by water, then ethyl acetate to obtainethyl3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylateas a yellow solid. The solid was dried in vacuum at 50° C. (140 mg,yield 18%). ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 1.18-1.21 (t, J=7.2 Hz,3H), 3.31 (s, 3H), 4.16-4.19 (m, 2H), 4.56-4.59 (d, J=13.2 Hz, 1H),5.14-5.17 (d, J=13.2 Hz, 1H), 6.54-6.56 (d, J=7.2 Hz, 1H), 6.72 (s, 1H),6.86 (s, 1H), 6.98-6.99 (d, J=4.8 Hz, 1H), 7.24-7.29 (m, 3H), 7.34-7.38(t, J=8.0 Hz, 1H), 7.42-7.44 (d, J=7.2 Hz, 2H), 7.49 (s, 1H); LC-MS(ESI) m/z: 376 (M+1)⁺.

Example 73B9-(1-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(140 mg) in 85% hydrazine monohydrate (3 mL) and methanol (5 mL) wasstirred at room temperature for 2 days. The resulting mixture wasfiltered and the residue was washed with water (20 mL) and methanol (5mL) to obtain a white solid. The solid was dried in vacuum at 50° C. toobtain9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(95 mg, yield 74%). ¹H-NMR (400 MHz, DMSO-d6) □δ (ppm): 3.40 (s, 3H),4.64-4.67 (d, J=10.8 Hz, 1H), 4.92-4.94 (d, J=10.4 Hz, 1H), 6.72 (s,1H), 6.87 (s, 1H), 7.15-7.17 (d, J=8.4 Hz, 2H), 7.26-7.30 (m, 3H), 7.38(s, 3H), 7.55-7.59 (t, J=7.6 Hz, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z:344 (M+1)⁺.

Example 748,9-Bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 74A Ethyl2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 mmol) and1-methyl-1H-imidazole-2-carbaldehyde (440 mg, 4 mmol) in ethylpropionate (20 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)] wasadded drop-wise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=5:1 to 1,ethyl acetate:methanol=50:1 to 25:1, ammonia hydrate 1 mL) to give ethyl2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg, yield 16%). LC-MS (ESI) m/z: 380 (M+1)⁺.

Example 74B8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (3 mL) wasstirred at room temperature for 3.5 h. Evaporated the solvent andmethanol (1 mL) was added, filtered and washed the cake by methanol (2mL) to obtain a white solid. The solid was dried in vacuum at 50° C. toobtain8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(45 mg, yield 41%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 3.46 (s, 3H), 3.49(s, 3H), 4.78-4.81 (d, J=12.0 Hz, 1H), 5.08-5.11 (d, J=12.0 Hz, 1H),6.69 (s, 1H), 6.76-6.79 (m, 3H), 6.99-7.02 (d, J=7.6 Hz, 1H), 7.42-7.49(m, 2H); LC-MS (ESI) m/z: 348 (M+1)⁺.

Example 759-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 75A9-(1-Benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100mL) was stirred at room temperature for 5 h. The resulting mixture wasfiltered to give9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a white solid (950 mg, yield 27%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):4.61-4.64 (d, J=11.2 Hz, 1H), 4.99-5.12 (m, 1H), 6.83-6.89 (m, 4H),7.14-7.28 (m, 11H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.54-7.58 (t, J=8.0 Hz,7H), 12.20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)⁺.

Example 75B9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(200 mg, 0.48 mmol), 20% Pd(OH)₂/C catalyst (100 mg) in methanol (15 mL)was purged with 1 atm hydrogen and stirred at 40° C. over overnight.Then the mixture solution was filtered and the filtrate was evaporatedunder reduced pressure. The residue was washed with methanol to obtain9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a light yellow solid (114 mg, yield 72%). ¹H-NMR (400 MHz, DMSO-d6)δ: 4.41-4.43 (d, J=8.0 Hz, 1H), 4.98-5.00 (d, J=8.8 Hz, 1H), 6.68-6.73(m, 1H), 6.86-6.97 (m, 1H), 7.12-7.14 (d, J=8.0 Hz, 1H), 7.20-7.37 (m,7H), 7.54-7.58 (t, J=8.0 Hz, 1H), 11.77 (s, 1H), 12.19 (s, 1H); LC-MS(ESI) m/z: 330 (M+1)⁺.

Example 769-(1-Ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 76A 1-Ethyl-1H-imidazole-2-carbaldehyde

To a suspension of 1H-imidazole-2-carbaldehyde (480 mg, 5 mmol) andpotassium carbonate (936 mg, 6 mmol) in N, N-dimethylformamide (7 mL)was added iodoethane (829 mg, 6 mmol) and the mixture was heated at 50°C. for 5 hrs. Solvent was removed under reduced pressure. The residuewas partitioned between water (30 mL) and ethyl acetate (30 mL). Theaqueous layer was extracted with ethyl acetate (20 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated to give 1-ethyl-1H-imidazole-2-carbaldehyde aslight yellow oil (520 mg, yield 84%). ¹HNMR (400 MHz, CDCl₃) δ (ppm):1.42-1.46 (t, J=7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, 1H), 7.29 (s,1H), 9.82 (s, 1H). LC-MS (ESI) m/z: 125 (M+1)⁺.

Example 76B Methyl3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

To 1-ethyl-1H-imidazole-2-carbaldehyde (520 mg, 4.19 mmol),(E)-4-(benzylideneamino) isobenzofuran-1(3H)-one (994 mg, 4.19 mmol),sodium methanolate (385 mg, 16.8 mmol) and ethyl propionate (15 mL) wereadded and the mixture was stirred at room temperature overnight. Thenthe resulting mixture was evaporated under reduced pressure andextracted with ethyl acetate (100 mL×4) and concentrated. The crudeproduct was purified by column chromatography (silica gel, petroleumether/ethyl acetate=20:1 to 5:1). 190 mg of methyl3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylatewas obtained. LC-MS (ESI) m/z: 390 (M+1)⁺.

Example 76C9-(1-Ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Methyl3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(190 mg, 0.49 mmol) and hydrazine monohydrate (2 mL) were added tomethanol (15 mL) and the mixture was stirred room temperature for 3 hrs.Methanol was evaporated and then filtered. The filtrate was concentratedto give9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a white solid (50 mg, yield 28%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):□0.96 (t, 3H), 3.74-3.79 (m, 2H), 4.61 (d, 1H), 4.95 (d, 1H), 6.78 (dd,1H), 6.91 (dd, 1H), 7.16 (d, 1H), 7.23-7.31 (m, 4H), 7.37 (s, 3H), 7.57(t, 1H). LC-MS (ESI) m/z: 358 (M+1)⁺.

Example 778-Phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 77A 1-propyl-1H-imidazole-2-carbaldehyde

1H-imidazole-2-carbaldehyde (800 mg, 8.3 mmol), 1-iodopropane (1.7 g, 10mmol) and potassium carbonate (1.4 g) were added in DMF (30 mL) and themixture was heated to 50° C. overnight. Then the mixture was evaporatedunder reduced pressure, and extracted with ethyl acetate (100 mL×4). Thecombined organic layers were dried over anhydrous sodium sulfate,concentrated to give 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g). LC-MS(ESI) m/z 139 (M+1)⁺.

Example 77B Ethyl4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

To the mixture of 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g, 8.0 mmol)and (E)-4-(benzylideneamino) isobenzofuran-1(3H)-one (1.7 g, 7.2 mmol)were added in ethyl propionate (50 mL) and then sodium methoxide wasadded under 0° C. The mixture was stirred overnight at room temperature.The mixture was concentrated and the residue was extracted with ethylacetate (100 mL×4). The organic layer dried over anhydrous sodiumsulfate, purified by chromatography (silica gel, petroleum ether/ethylacetate=10:1 to 1:1) to give ethyl4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(770 mg, yield 30%). LC-MS (ESI) m/z: 404 (M+1)⁺.

Example 77C8-Phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A suspension of ethyl4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(770 mg, 1.9 mmol) and hydrazine monohydrate (6 mL, 85%) were added inmethanol (10 mL) and stirred at 50° C. overnight. The mixture wasfiltered, and the white solid was washed with methanol and dried invacuum to obtain8-phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(260 mg, yield 37%). ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 0.59-0.62 (t,J=7.4 Hz, 1H), 1.23-1.40 (m, 2H), 3.62-3.72 (m, 2H), 4.58-4.61 (d,J=11.2 Hz, 1H), 4.97-4.99 (d, J=11.2 Hz, 1H), 6.79 (s, 1H), 6.89 (s,1H), 7.16-7.59 (m, 8H), 12.15 (s, 1H); LC-MS (ESI) m/z: 372 (M+1)⁺.

Example 789-(1-Methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 78A Ethyl3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino) isobenzofuran-1(3H)-one (474 mg, 2mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (220 mg, 2 mmol) in ethylpropionate (20 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)] wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=5:1 to 3:7) togive ethyl3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(170 mg, yield 23%). LC-MS (ESI) m/z: 376 (M+1)⁺.

Example 78B9-(1-Methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(170 mg) in 85% hydrazine monohydrate (3 mL) and methanol (3 mL) wasstirred at room temperature for 5 h. Filtered and washed the cake bymethanol (2 mL) to obtain a white solid. The solid was dried in vacuumat 50° C. to obtain9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(70 mg, yield 46%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H),4.52-4.54 (d, J=9.2 Hz, 1H), 4.83-4.85 (d, J=9.2 Hz, 1H), 6.66 (s, 1H),7.17-7.19 (d, J=7.6 Hz, 1H), 7.25-7.32 (m, 3H), 7.36-7.44 (m, 5H),7.56-7.60 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 348 (M+1)⁺.

Example 799-(3-((Diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde(200 mg, 0.5 mmol) and diethylamine (146 mg, 2.0 mmol) in methanol (10mL) was stirred at room temperature for 40 min. Then the mixture wascooled to 0° C. Sodium borohydride (56 mg, 1.5 mmol) was added. Afterthe addition, the mixture was stirred at room temperature for 2 hr.Methanol was removed under reduced pressure. The residue was washed withethyl acetate and filtered. The filtrate was concentrated to give thecrude product. The crude product was purified by prep-HPLC to give9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a white solid (76 mg, yield 29%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm):1.28-1.33 (m, 12H), 3.13-3.19 (m, 8H), 4.27 (s, 4H), 4.40-4.42 (d, J=7.6Hz, 1H), 4.84-4.86 (d, J=7.6 Hz, 1H), 7.22-7.27 (m, 3H), 7.38-7.41 (m,6H), 7.56-7.65 (m, 2H); LC-MS (ESI) m/z: 510 (M+1)⁺.

Example 80 9-(3-((Methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(150 mg, 0.4 mmol) in dryness dichloromethane (10 mL) was added aceticacid followed by 1-methylpiperazine (121 mg, 1.2 mmol). After theaddition, the mixture was stirred at room temperature for 1 h, Then themixture was cooled to 0° C. Sodium borohydride (130 mg, 0.2 mmol) wasadded. After the addition, the mixture was stirred at this temperaturefor 3 hr. Dichloromethane was removed under reduced pressure. Theresidue was washed with ethyl acetate/methanol (10/1) and filtered. Thefiltrate was concentrated to give the crude product. The crude productwas purified by pre-HPLC to give 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas white solid (22 mg, yield 12%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.31(s, 3H), 2.36-2.48 (m, 8H), 3.37-3.48 (dd, 2H), 4.30 (dd, 1H), 4.71 (dd,1H), 7.01 (s, 1H), 7.05 (dd, 1H), 7.17-7.23 (m, 5H), 7.25-7.28 (m, 2H),7.56 (dd, 1H), 7.61-7.65 (t, 1H); LC-MS (ESI) m/z: 452 (M+1)⁺.

Example 81 8-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 81A Methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

4-Aminoisobenzofuran-1(3H)-one (372.5 mg, 2.5 mmol),4-(4-(cyclopropanecarbonyl) piperazine-1-carbonyl) benzaldehyde (645 mg,2.5 mmol) and 1 g of MgSO₄ were added into 40 mL of dichloromethane andstirred under reflux overnight, then the mixture was evaporated underreduced pressure and the residues was dried in vacuum. 385 mg of(E)-4-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzylideneamino)isobenzofuran-1(3H)-one. Amixture of (E)-4-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzylideneamino)isobenzofuran-1(3H)-one (385 mg,0.92 mmol), benzaldehyde (97.9 mg, 0.97 mmol), sodium methanolate (199mg, 3.68 mmol) and ethyl propionate (10 mL) was stirred at roomtemperature overnight. Then the resulting mixture was evaporated underreduced pressure and extracted with ethyl acetate (100 mL×4) andconcentrated. The crude product was purified by column chromatography(silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to give 300 mgof methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate.LC-MS (ESI) m/z: 538 (M+1)⁺.

Example 81B 8-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(300 mg, 0.55 mmol) and hydrazine monohydrate (3 mL) was stirred roomtemperature for 3 h. The resulting mixture was evaporated under reducedpressure to 10 mL and then filtered; the filtrate was concentrated togive the crude product. The crude product was purified by pre-HPLC togive 8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneas a white solid (4 mg, yield 19%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):□0.71-0.74 (m, 4H), 1.97 (t, 1H), 3.46-3.76 (m, 8H), 4.36 (dd, 1H), 4.83(dd, 1H), 7.13-7.23 (m, 6H), 7.30 (d, 2H), 7.38 (t, 3H), 7.47 (s, 1H),7.59 (t, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 520 (M+1)⁺.

Example 829-Phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 82A Ethyl4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(pyridin-4-ylmethyleneamino) isobenzofuran-1(3H)-one(1.71 g, 7.18 mmol) and benzaldehyde (837 mg, 7.9 mmol) in ethylpropionate (50 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol [sodium (660 mg, 28.7 mmol) in ethanol (35 mL)] wasadded drop-wise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (20 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (150 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=5:1 to 1:1) togive ethyl4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(340 mg, yield 13%). LC-MS (ESI) m/z: 373 (M+1)⁺.

Example 82B9-Phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(340 mg) in 85% hydrazine monohydrate (6 mL) and methanol (3 mL) wasstirred at room temperature for 2 h. After the evaporation of thesolvent, water was added. Filtered and washed the cake by water (5 mL)then ethyl acetate to obtain a white solid. The solid was dried invacuum at 50° C. to obtain9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(150 mg, yield: 48%). ¹H-NMR (400 MHz, DMSO-d6) □ δ (ppm): 4.38-4.40 (d,J=7.6 Hz, 1H), 4.84-7.86 (d, J=8.0 Hz, 1H), 7.15-7.25 (m, 6H), 7.30-7.31(m, 2H), 7.39-7.41 (d, J=7.6 Hz, 1H), 7.51-7.52 (s, 1H), 7.59-7.62 (t,J=8.0 Hz, 1H), 8.43-8.44 (d, J=6.0 Hz, 2H) 12.19 (s, 1H); LC-MS (ESI)m/z: 341 (M+1)⁺.

Example 839-Phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

The mixture of9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(150 mg, 0.4 mmol), con.HCl (0.6 mL) and Platinum (IV) oxide monohydrate(40 mg) in methanol (30 mL) was purged with 50 atm of hydrogen at 50° C.for 18 h. Then the mixture was filtered. The solvent was removed invacuum to obtain a crude oil which was purified by prep-HPLC to give9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(95 mg, yield 62%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.24-1.41 (m,1H), 1.49-1.59 (m, 1H), 1.69-1.78 (m, 2H), 1.98-2.01 (d, J=13.2 Hz, 1H),2.67-2.86 (m, 2H), 3.22-3.31 (m, 3H), 4.18 (s, 1H), 7.05-7.08 (m, 3H),7.14-7.21 (m, 2H), 7.24-7.28 (m, 2H), 7.31-7.33 (d, J=7.2 Hz, 1H),7.52-7.56 (t, J=8.0 Hz, 1H), 8.19-8.24 (m, 1H), 8.54-8.56 (m, 1H), 12.30(s, 1H); LC-MS (m/z) 347 (M+1)⁺.

Example 849-Phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 84A Methyl4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), picolinaldehyde (856mg, 8 mmol) and 1 g of MgSO₄ were added into 40 mL of dichloromethaneand the mixture was stirred under reflux overnight, then the mixture wasevaporated under reduced pressure and the residues was dried in vacuum.476 mg of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one wasobtained. A mixture of (E)-4-(pyridin-2-ylmethyleneamino)isobenzofuran-1(3H)-one (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol),sodium methanolate (432 mg, 8 mmol) and ethyl propionate (40 mL) wasstirred at room temperature overnight. Then the resulting mixture wasevaporated under reduced pressure and extracted with ethyl acetate (100mL×4) and concentrated. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1)to give 30 mg of methyl4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate;yield 5%. LC-MS (ESI) m/z: 459 (M+1)⁺.

Example 84B9-Phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(30 mg, 0.08 mmol) and hydrazine monohydrate (1 mL) was stirred at roomtemperature for 3 h. The resulting mixture was evaporated under reducedpressure to 10 mL and then filtered, 10 mg of9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas obtained, yield 37%. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 4.60 (d, 1H),4.86-4.88 (m, 1H), 5.21 (s, 1H), 6.96 (dd, 1H), 7.08-7.17 (m, 4H),7.22-7.28 (m, 3H), 7.46-7.49 (m, 1H), 7.60 (t, 1H), 7.73 (dd, 1H), 8.59(d, 1H), 9.77 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)⁺.

Example 858-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(150 mg, 0.4 mmol), N-methyl-piperazine (123 mg, 1.2 mmol) and aceticacid (120 mg, 1.2 mmol) in methanol (50 mL) was stirred at roomtemperature for 60 min. Then the mixture was cooled to 0° C. Sodiumtriacetoxyborohydride (130 mg, 0.6 mmol) was added. After the addition,the mixture was stirred at room temperature for overnight. Methanol wasremoved under reduced pressure. The crude product was purified bypre-HPLC to give8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(36 mg, yield 19%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.29 (s, 3H),2.12-2.73 (br s, 8H), 3.47 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d,J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.18-7.21 (m, 6H), 7.23-7.25 (m, 2H),7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 452(M+1)⁺.

Example 868,9-Bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 86A Methyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate,ethyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand methyl2,3-bis-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (1.36g, 4 mmol), 4-fluorobenzaldehyde (546 mg, 4.4 mmol), sodium methanolate(864 mg, 16 mmol) and ethyl propionate (25 ml) was stirred at roomtemperature overnight. Then the resulting mixture was evaporated underreduced pressure and extracted with ethyl acetate (100 mL×4) andconcentrated. The crude product was purified by column chromatography(silica gel, petroleum ether:ethyl acetate=20:1 to 1:1) to give 440 mgof a mixture of methyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate,ethyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand methyl2,3-bis-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate.

Example 86B8,9-Bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate,ethyl2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand methyl2,3-bis-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(440 mg) and hydrazine monohydrate (20 mL) was stirred under roomtemperature for overnight. The resulting mixture was evaporated underreduced pressure to 10 mL and then filtered, 400 mg of the crudeproducts were obtained. To a solution of this crude products (400 mg) indichloromethane was added trifluoroacetic acid (1 ml) at 0° C. Themixture was stirred at room temperature for 1 hr. Then the mixture wasneutralized with potassium carbonate. The mixture was extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to give thecrude. The crude product was purified by column chromatography (silicagel, petroleum ether:ethyl acetate 10:1 to 1:1) to give4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg) and8,9-bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(36 mg).4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde:LC-MS (ESI) m/z: 368 (M+1)⁺.8,9-bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:¹H-NMR (400 MHz, CD₃OD) δ (ppm): □4.29 (d, J=8.0 Hz, 1H), 4.70 (d, J=8.0Hz, 1H), 6.92-7.00 (m, 4H), 7.08-7.10 (m, 2H), 7.20-7.20 (m, 1H),7.28-7.32 (m, 2H), 7.59 (m, 1H), 7.63-7.67 (m, 1H). ¹⁹F-NMR (400 MHz,CD₃OD) δ (ppm): −116.77, −118.23; LC-MS (ESI) m/z: 376 (M+1)⁺. solid.

Example 878-(4-((Dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.21 mmol), dimethlyamine (47 mg, 1.04 mmol) and acetic acid (62mg, 1.04 mmol) in methanol (50 mL) was stirred at room temperature for60 min. Then the mixture was cooled to 0° C. Sodium cyanoborohydride (20mg, 0.3 mmol) was added. After the addition, the mixture was stirred atroom temperature for overnight. Methanol was removed under reducedpressure. The crude product was purified by pre-HPLC to give8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(21 mg, yield 24%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.82 (s, 6H), 4.26(s, 2H), 4.32 (d, J=8.0 Hz, 1H), 4.77 (d, J=8.0 Hz, 1H), 6.93-6.95 (m,2H), 7.10-7.11 (m, 2H), 7.23 (m, 1H), 7.40-7.41 (m, 4H), 7.59 (d, J=8.0Hz, 1H), 7.65 (t, J=8.0 Hz, 1H). ¹⁹F-NMR (400 MHz, CD₃OD) δ (ppm):−77.09, −118.00; LC-MS (ESI) m/z: 415 (M+1)⁺.

Example 888-(4-Fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 88A Ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a stirred mixture of 4-fluorobenzaldehyde (3 g, 20.4 mmol) andanhydrous sodium sulfate (29 g, 20.4 mmol) in anhydrous dichloromethane(200 mL) was added 4-aminoisobenzofuran-1(3H)-one (3.04 g, 24.5 mmol) at0° C. After the addition, the mixture was stirred at room temperaturefor 6 days. The mixture was filtered and the cake was washed withdichloromethane (50 mL×3). The filtrate was concentrated to give crudeproduct. The crude product was washed with petroleum ether to give(E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (4.25 g, yield81%); LC-MS (ESI) m/z: 256 (M+1)⁺. A mixture of(E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (2.53 g, 10mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1.21 g, 11 mmol) inethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodiumethanoxide in ethanol [sodium (1 g, 44 mmol) in ethanol (30 mL)] wasadded drop-wise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(210 mg, yield 5%). LC-MS (ESI) m/z: 394 (M+1)⁺.

Example 88B8-(4-Fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(210 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) wasstirred at 45° C. for overnight. Methanol was removed under reducedpressure. The mixture was filtered and washed with water to give8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one36 mg, yield 19%). ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 3.42 (s, 3H),4.66 (d, J=8.0 Hz, 1H), 4.95 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.89 (s,1H), 7.11-7.17 (m, 3H), 7.30 (s, 1H), 7.40 (d, 1H), 7.43-7.44 (m, 2H),7.58 (d, 1H), 12.17 (s, 1H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ (ppm):−114.58; LC-MS (ESI) m/z: 362 (M+1)⁺.

Example 898,9-Bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 89A 3-(Diethoxymethyl)benzaldehyde

A mixture of isophthalaldehyde (21.44 g, 160 mmol), ammonium chloride(0.34 g, 6.38 mmol) in anhydrous ethanol (23.2 g, 480 mmol) was cooledto 0° C., then triethyl orthoformate was added drop-wise. After theaddition, the mixture was warmed to 40° C. and stirred for two days. Themixture was filtered and the filtrate was concentrated to give crudeproduct. The crude product was purified by column chromatography (silicagel, petroleum ether/ethyl acetate=200:1 to 100:1) to give3-(diethoxymethyl)benzaldehyde (25.4 g, yield 76%) as a colorless oil.¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.23-1.27 (m, 6H), 3.53-3.67 (m, 4H),5.58 (s, 1H), 7.52-7.56 (t, J=7.6 Hz, 1H), 7.74-7.77 (dd, J₁=7.6 Hz,J_(2=3.6) Hz, 1H), 8.00 (s, 1H), 10.04 (s, 1H); LC-MS (ESI) m/z: 209(M+1)⁺.

Example 89B Methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 mmol) and3-(diethoxymethyl)benzaldehyde (0.83 g, 4 mmol) in ethyl propionate (15mL) was cooled to 0° C. Then a solution of sodium methoxide in methanol[sodium (184 mg, 8 mmol) in methanol (15 mL)] was added drop-wise. Afterthe addition, the mixture was stirred at 25° C. for 18 hr. The mixturewas quenched with water (10 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give crude product.The crude product was purified by chromatography (silica gel, petroleumether/ethyl acetate=100:1 to 10:1) to give a mixture of methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(370 mg together, yield 33%) as light yellow solid. LC-MS (ESI) m/z: 562(M+1)⁺, 576 (M+1)⁺.

Example 89C8,9-Bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of methyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylateand ethyl2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL)was stirred at 50° C. for 2 hr. The mixture was cooled to roomtemperature and filtered to give8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(250 mg, yield 77%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm): 0.99-1.08 (m, 12H), 3.27-3.33 (m, 8H), 4.28-4.31 (d, J=8.8 Hz,1H), 4.74-4.76 (d, J=8.4 Hz, 1H), 5.31-5.32 (d, J=6.8 Hz, 2H), 7.04 (s,1H), 7.12-7.26 (m, 7H), 7.31-7.43 (m, 3H), 7.56-7.60 (t, J=8.0 Hz, 1H);LC-MS (ESI) m/z: 544 (M+1)⁺.

Example 89D3,3′-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde

A mixture of8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at roomtemperature for 2 hr. Then the mixture was adjusted to pH=8 withpotassium carbonate. The resulting suspension was filtered to give3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde(160 mg, yield 88%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm): 4.57-4.59 (d, J=9.6 Hz, 1H), 4.98-5.00 (d, J=9.2 Hz, 1H),7.20-7.22 (d, J=7.6 Hz, 1H), 7.42-7.52 (m, 5H), 7.60-7.77 (m, 5H), 7.89(s, 1H), 9.90 (s, 1H), 9.93 (s, 1H), 12.08 (s, 1H); LC-MS (ESI) m/z: 396(M+1)⁺.

Example 89E8,9-Bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde(60 mg, 0.16 mmol) and 32% dimethylamine solution (135 mg, 0.96 mmol) inmethanol (10 mL) was stirred at room temperature for 40 min. Then themixture was cooled to 0° C. Sodium borohydride (18.2 mg, 0.48 mmol) wasadded. After the addition, the mixture was stirred at room temperaturefor 2 hr. Methanol was removed under reduced pressure. The residue waswashed with ethyl acetate and filtered. The filtrate was concentrated togive the crude product. The crude product was purified by prep-HPLC togive8,9-bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(18.6 mg, yield 26%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.61-2.67 (m, 12H), 4.10-4.15 (m, 4H), 4.25-4.27 (d, J=9.6 Hz,1H), 4.67-4.69 (d, J=10.0 Hz, 1H), 7.05-7.29 (m, 7H), 7.29-7.39 (m, 2H),7.49-7.54 (m, 2H); LC-MS (ESI) m/z: 454 (M+1)⁺.

Example 909-(34(Cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde(70 mg, 0.19 mmol) and cyclopropanamine (32.55 mg, 0.57 mmol) inanhydrous methanol (10 mL) was stirred at room temperature for 1.5 h.Then the mixture was cooled to 0° C., sodium borohydride (10.82 mg,0.286 mmol) was added portion-wise. After the addition, the mixture wasstirred at this temperature for 2 hr. Methanol was removed under reducedpressure. The residue was dissolved in ethyl acetate (50 mL), extractedwith 1N hydrochloric acid (20 mL), the aqueous layer was separated. Theorganic layer was washed with 1N hydrochloric acid (20 mL). The combinedaqueous layers were adjusted to pH=9 with potassium carbonate, extractedwith ethyl acetate (25 mL×4). The combined organic layers were driedover anhydrous sodium sulfate, and concentrated to give9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(15 mg, yield 19%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 0.19-0.29 (m, 4H), 1.74-1.80 (m, 1H), 3.55 (s, 2H), 4.16-4.19 (d,J=8.8 Hz, 1H), 4.60-4.62 (d, J=8.8 Hz, 1H), 6.88-6.90 (d, J=7.6 Hz, 1H),6.95 (s, 1H), 7.01-7.10 (m, 6H), 7.13-7.15 (m, 2H), 7.42-7.44 (d, J=7.6Hz, 1H), 7.48-7.75 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 408 (M+1)⁺.

Example 918-(3-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(50 mg, 0.14 mmol) and 1M dimethylamine methanol solution (0.5 ml, 0.41mmol) in methanol (10 mL) was stirred at room temperature for 40 min.Then the mixture was cooled to 0° C. Sodium cyanoborohydride (13 mg,0.20 mmol) and acetic acid (40.8 mg, 0.68 mmol) was added. After theaddition, the mixture was stirred at 0° C. for 2 hr. Methanol wasremoved under reduced pressure. The residue was resolved with 1Nhydrochloric acid and washed with ethyl acetate. The mother liquor wasadjusted to pH=8 and extracted with ethyl acetate. The solvent wasremoved to give8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(34 mg, yield 64%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.17 (s, 6H), 3.17-3.41 (q, 2H), 4.31 (d, J=8.0 Hz, 1H), 4.74 (d,J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.25 (m, 8H), 7.55-7.57 (d, J=8.0Hz, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 397 (M+1)⁺.

Example 928-(3-(Morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(40 mg, 0.11 mmol), morpholine (28 mg, 0.33 mmol) and acetic acid (33mg, 0.55 mmol) in methanol (50 mL) was stirred at room temperature for40 min. Then the mixture was cooled to 0° C. Sodiumtriacetoxyborohydride (35 mg, 0.16 mmol) was added. After the addition,the mixture was stirred at 0° C. for 2 hr. Methanol was removed underreduced pressure. The residue was resolved with 1N hydrochloric acid andwashed with ethyl acetate. The mother liquor was adjusted to pH=8 andextracted with ethyl acetate. The solvent was removed to give8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(31 mg, yield 66%) as a light yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.23-2.24 (m, 4H), 3.32-3.43 (q, 2H), 4.30 (d, J=8.0 Hz, 1H),4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.19 (m, 6H), 7.21-7.25(m, 1H), 7.31-7.33 (m, 1H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m,1H). LC-MS (ESI) m/z: 439 (M+1)⁺.

Example 938-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 93A Ethyl2-(4-(diethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A solution of(E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (10.8g, 31.9 mmol) and 4-fluorobenzaldehyde (3.95 g, 31.9 mmol) in ethylpropionate (150 mL) was added sodium ethoxide (8.66 g, 127.4 mmol, inethanol 60 ml) at 0° C. Then the mixture was stirred at room temperaturefor 5 hr. The resulting mixture was evaporated under reduced pressureand extracted with ethyl acetate (100 mL×4) and concentrated. The crudeproduct was purified by column chromatography (silica gel, petroleumether:ethyl acetate=20:1 to 1:1) to give the crude product (4.2 g, yield26%). LC-MS (ESI) m/z: 492 (M+1)⁺.

Example 93B8-(4-(Diethoxymethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

The crude compound ethyl2-(4-(diethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(4.2 g, 8.54 mmol) and hydrazine monohydrate (5 mL) were added inmethanol (60 mL) and the mixture was stirred at room temperature for 16hr. The resulting mixture was concentrated under reduced pressure to avolume of 40 mL and then filtered to obtain the crude title compound(3.0 g, yield 76%). LC-MS (ESI) m/z: 460 (M+1)⁺.

Example 93C4-(9-(4-Fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

To a solution of the crude8-(4-(diethoxymethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(3.0 g, 6.53 mmol) in water (10 mL) was addedhydrochlorichlip://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure._structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3acid (1 N, 50 mL) at 0° C. The mixture was stirred at room temperaturefor 4 hr. Then the mixture was neutralized with potassium carbonate. Themixture was extracted with ethyl acetate (200 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated to give the crude title compound (2.5 g, yield98%). LC-MS (ESI) m/z: 386 (M+1)⁺.

Example 93D8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of the crude4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(930 mg, 2.42 mmol) in DCM (120 mL) was added acetic acid (0.3 mL)followed by azetidine (670 mg, 11.8 mmol), after the addition, themixture was stirred at room temperature overnight. Then the mixture wascooled to 0° C. and NaBH(OAc)₃(764 mg, 3.62 mmol) was added. After theaddition, the mixture was stirred at this temperature for 6 hr. DCM wasremoved under reduced pressure. The residue was added water followed byhydrochlorichlip://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure._structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3acid (5 mL) at 25° C. The mixture was stirred at room temperature for0.5 hr. The mixture was extracted with ethyl acetate (100 mL×3). Thewater layer was neutralized with potassium carbonate and filtered toobtain the title compound as a white solid (500 mg, yield 49%). LC-MS(ESI) m/z: 427 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.24-2.49 (m,2H), 3.85-4.02 (m, 4H), 4.25 (d, 2H), 4.38 (d, 1H), 4.80 (d, 1H) 7.03(t, 2H), 7.14-7.20 (m, 3H), 7.36-7.39 (m, 5H), 7.47 (s, 1H), 7.59 (t,1H) 10.64 (s, 1H), 12.18 (s, 1H).

Example 945-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 94A Ethyl7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-6-fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (4 g,14.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (4.1 g, 36.9mmol) in ethyl propionate (220 mL) was added EtONa ((sodium 940 mg, 40.9mmol), in 70 mL ethanol) at 37° C., then the mixture was stirred at 40°C. for 6 hr. The resulting mixture was evaporated under reduced pressureand extracted with ethyl acetate (100 mL×4).The extract was concentratedto dryness to give a crude product, which was purified by columnchromatography (silica gel, dichloromethane:methanol=200:1 to 100:1) toobtain a green solid (1.02 g, yield 14%). LC-MS (ESI) m/z: 413 (M+1)⁺.

Example 94B5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(840 mg, 2.04 mmol) in methanol (2 mL) was added hydrazine monohydrate(1 mL), and the mixture was stirred under 25° C. for 10 hr. Then themixture was filtered to obtain a white solid (650 mg, yield 84%). LC-MS(ESI) m/z: 381 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□ δ (ppm): 3.66 (s,3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J₁=11.2 Hz, J₂=2.4 Hz, 1H),7.06-7.09 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51(m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H)

Example 959-(1-Methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 95A Ethyl3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (1.78g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9.16mmol) in ethyl propionate (110 mL) was added EtONa (sodium (490 mg, 21mmol) in 35 mL ethanol) at 40° C., then the mixture was stirred at 41°C. for 3 hr. The resulting mixture was evaporated under reduced pressureand extracted with ethyl acetate (150 mL×4) and concentrated. The crudeproduct was purified by column chromatography (silica gel,dichloromethane:methanol=200:1 to 50:1) to obtain a green solid (400 mg,yield 14%). LC-MS (ESI) m/z: 377 (M+1)⁺.

Example 95B9-(1-Methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(400 mg, 1.06 mmol) in methanol (8 mL) was added hydrazine monohydrate(0.5 mL), and the mixture was then stirred at 25° C. for 10 hr. Themixture was filtered to obtain a white solid (110 mg, yield 30%). LC-MS(ESI) m/z: 345 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□δ (ppm): 3.77 (s,3H), 4.48-4.49 (d, J=6.4 Hz, 1H), 5.16-5.19 (d, J=6.4 Hz, 1H), 7.40-7.42(m, 2H), 7.54-7.58 (t, 1H), 7.74 (s, 1H), 12.23 (s, 1H).

Example 968-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 96A Ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(2.21 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01g, 9.16 mmol) in ethyl propionate (110 ml) was added rapidly EtONa(sodium (490 mg, 21 mmol) in 35 mL ethanol) at 40° C., then the mixturewas stirred at 45° C. for 3 hr. The resulting mixture was evaporatedunder reduced pressure, extracted with ethyl acetate (200 mL×3), andthen concentrated the extract. The crude product was purified by columnchromatography (silica gel, dichloromethane:methanol=100:1 to 10:1) toobtain a green solid (510 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)⁺.

Example 96B8-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(506 mg, 1.17 mmol) in methanol (3 mL) was added hydrazine monohydrate(1 mL), and the mixture was stirred at 25° C. for 10 hrs. The mixturewas filtered to obtain a white solid (225 mg, yield 48%). LC-MS (ESI)m/z: 402 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□δ (ppm): 2.10 (s, 6H), 3.33(s, 2H), 3.58 (s, 3H), 4.88-4.92 (m, 2H), 7.20-7.22 (m, 3H), 7.34-7.40(m, 4H), 7.54-7.62 (t, J=8.4 Hz, 1H), 7.79 (s, 1H), 12.20 (s, 1H).

Example 978-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 97A Ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one(2.34 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01g, 9.16 mmol) in ethyl propionate (110 mL) was added EtONa (sodium (500mg, 21 mmol) in 35 mL ethanol) at 40° C., then the mixture was stirredat 48° C. for 3 hr. The resulting mixture was evaporated under reducedpressure, extracted with ethyl acetate (250 mL×3), and concentrated. Thecrude product was purified by column chromatography (silica gel,dichloromethane:methanol=50:1 to 10:1) to obtain a green solid (160 mg,yield 4.7%). LC-MS (ESI) m/z: 452 (M+1)⁺.

Example 97B8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(160 mg, 0.35 mmol) in methanol (2 mL) was added hydrazine monohydrate(0.5 mL), and the mixture was stirred at 25° C. for 10 hr. The mixturewas filtered to obtain the title compound as a white solid (45 mg, yield30%). LC-MS (ESI) m/z: 420 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□δ (ppm):2.10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H), 4.91-4.99 (m, 2H), 6.91-6.95(dd, J₁=11.2 Hz, J₂=2.4 Hz, 1H), 7.05-7.08 (dd, J₁=9.2 Hz, J₂=2.4 Hz,1H), 7.20-7.23 (d, J=8.0 Hz, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.72 (s,1H), 7.79 (s, 1H), 12.33 (s, 1H).

Example 988-(4-Fluorophenyl)-9-methyl-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 98A Ethyl2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A solution of ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(100 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.51 mmol) inN,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr.Then the solution was cooled to 0° C. and a solution of iodomethane (0.1mL) in N,N-dimethylformamide (1 mL) was added dropwise at 0° C. over 1hr, stirred at room temperature overnight. The mixture was quenched withwater (30 mL), extracted with ethyl acetate, washed with brine, and thenthe extraction was evaporated to get the crude product, which was usedin next step without further purification (80 mg, yield 77%). LC-MS(ESI) m/z: 409 (M+1)⁺.

Example 98B8-(4-Fluorophenyl)-9-methyl-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(80 mg, 0.19 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (1mL) was stirred under reflux overnight. The resulting solution wascooled and filtered, washed the cake by methanol (2 mL) to obtain awhite solid, dried in vacuum at 55° C. to obtain the title compound (40mg, yield 54%). LC-MS (ESI) m/z: 377 (M+1)⁺; ¹H-NMR (400 MHz, DMSO-d6)□δ (ppm): 1.83 (s, 3H), 2.86 (s, 3H), 4.61 (s, 1H), 6.88-6.92 (m, 2H),7.11-7.169 (t, J=8.8 Hz, 2H), 7.19-7.22 (d, J=8.0 Hz, 1H), 7.41 (s, 1H),7.47-7.49 (m, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H), 7.72 (s, 1H), 12.40 (s,1H).

Example 998-(4-Fluorophenyl)-9-(1,4,5-trimethyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 99A 1,4,5-Trimethyl-1H-imidazole

To a cold suspension of formaldehyde (21 mL, 0.3 mol), methylaminehydrochloride (36.5 g, 540 mmol) and ammonium hydroxide (150 mL) wasadded butandione (15.8 mL, 180 mmol) and the mixture was then stirred at100° C. for 30 min. After cooled to room temperature the reactionmixture was extracted with dichloromethane. The organic layers weredried with Na₂SO₄ and the solvent was removed via rotary evaporation.The crude was purified by chromatography(dichloromethane/methanol=100:1) to give 1,4,5-trimethyl-1H-imidazole.¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.11 (s, 3H), 2.15 (s, 3H), 3.49 (s,3H), 7.28 (s, 1H).

Example 99B 1,4,5-Trimethyl-1H-imidazole-2-carbaldehyde

To a solution of 1,4,5-trimethyl-1H-imidazole (550 mg, 5 mmol) in drytetrahydrofuran (15 mL) was added dropwise n-BuLi (3 mL, 2.5 M inhexane) at −40° C. After stirring for 2 h at this temperature, to thesolution was added dried DMF (840 mg, 11.5 mmol) at −70° C. Theresulting yellow suspension was stirred at −70° C. for 1 h, then at 0°C. for 0.5 h and quenched with ice-water. The mixture was extracted withethyl acetate, and the organic extracts were dried with Na₂SO₄ beforeevaporation to afford an oily residue. The residue was purified bysilica column (petroleum ether:ethyl acetate=3:1) to obtain 340 mg ofwhite solid, yield: 50%. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.21 (s, 1H),2.25 (s, 1H), 3.90 (s, 1H), 9.66 (s, 1H). LC-MS (ESI) m/z: 138 (M+1)⁺.

Example 99C Ethyl2-(4-fluorophenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound(E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (510 mg, 2.0mmol) and 1,4,5-trimethyl-1H-imidazole-2-carbaldehyde (304 mg, 2.2 mmol)in ethyl propionate (20 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol (sodium (184 mg, 8.0 mmol) in ethanol (10mL)) was added dropwise. After the addition, the mixture was stirred atroom temperature for 2.5 hr. The mixture was quenched with water (20 mL)and solvent was removed under reduced pressure. The residue wasdissolved in water and extracted with ethyl acetate (100 mL×3), then theextraction was washed with water, brine and evaporated, the crudeproduct was purified by chromatography to obtain a yellow solid (150 mg,yield: 18%). LC-MS (ESI) m/z: 421 (M+1)⁺.

Example 99D8-(4-Fluorophenyl)-9-(1,4,5-trimethyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg) in 85% hydrazine monohydrate (85%, 3 mL) and methanol (5 mL)was stirred at room temperature for 2 days. The result suspension wasfiltered and washed the water (20 mL) and methanol (5 ml) to obtain awhite solid. The solid was dried in vacuum at 50° C. to afford the titlecompound (90 mg, yield 65%). ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):1.91-1.96 (d, J=18 Hz, 6H), 3.25 (s, 3H), 4.59-4.62 (d, J=10.8 Hz, 1H),4.92-4.95 (d, J=10.8 Hz, 1H), 7.09-7.15 (m, 3H), 7.22 (s, 1H), 7.36-7.38(d, J=7.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.54-7.58 (t, J=8 Hz, 1H), 12.13(s, 1H); LC-MS (ESI) m/z: 390 (M+1)⁺.

Example 1008-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,3-triazol-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 100A (1H-1,2,3-Triazol-4-yl)methanol

TMSN₃ (24.8 g, 214 mmol) was added to a solution of CuI (1.4 g, 0.4 mol)and prop-2-yn-1-ol (8.0 g, 142.4 mmol) in DMF (160 mL) and methanol (20mL) under nitrogen atmosphere. The reaction mixture was stirred at 100°C. for 12 h. Then the mixture was cooled to room temperature andfiltered through a short florisil and concentrated. The crude waspurified by column chromatography (silica gel, pre-washed withtriethylamine, petroleum ether:ethyl acetate 1:3 to 1:5) to give thetitle compound (12.7 g, 90%) as a yellow oil. ¹H-NMR (400 MHz, DMSO-d6)□□ δ (ppm): 4.09 (m, 2H), 4.48-4.10 (m, 1H), 5.21-5.24 (m, 1H), 7.62 (s,1H); LC-MS (ESI) m/z: 100 (M+1)⁺.

Example 100B (1-Methyl-1H-1,2,3-triazol-4-yl)methanol

To a solution of (1H-1,2,3-triazol-4-yl)methanol (5.0 g, 51.5 mmol) andK₂CO₃(8.5 g, 62 mmol) in MeCN (190 mL) was added methyl iodine (3.8 ml)dropwise at 0° C. Then the reaction was stirred at room temperatureovernight, the reaction solution was filtrated, and adjusted to pH=6with acetic acid, then the solvent was evaporated to obtain the titlecompound (5.6 g, yield 98%) as yellow oil and used in next step withoutfurther purification. LC-MS (ESI) m/z: 114 (M+1)⁺.

Example 100C 1-Methyl-1H-1,2,3-triazole-4-carbaldehyde

(1-Methyl-1H-1,2,3-triazol-4-yl)methanol (5.6 g, 50 mmol) and activatedmanganese dioxide (55 g, 65 mmol) was dissolved in acetone (130 mL) andthe solution was stirred at room temperature for 3 h. Then the reactionmixture was filtered, the solvent was evaporated in vacuum. The residuewas purified by flash chromatography (silica gel, petroleum ether:ethylacetate 5:1 to 2:1) to obtain the title compound (1.1 g, yield 20%).¹H-NMR (400 MHz, DMSO-d6) □□ δ (ppm): 4.13 (m, 3H), 8.81 (s, 1H), 10.02(s, 1H); LC-MS (ESI) m/z: 112 (M+1)⁺.

Example 100D Ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one(698 mg, 2.7 mmol) and 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (334mg, 3 mmol) in ethyl propionate (35 mL) was cooled to 0° C. Then asolution of sodium ethanolate in ethanol (sodium (248 mg, 10.8 mmol) inethanol (15 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 4 hr. The mixture was quenched withwater (10 mL) and solvent was removed in vacuum. The residue wasdissolved in water, and then extracted with ethyl acetate (100 mL×4).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated to give crude product, which then waspurified by chromatography (silica gel, petroleum ether/ethylacetate=3:1 to 1:1) to give the title compound (426 mg, yield 39%).LC-MS (ESI) m/z: 395 (M+1)⁺.

Example 100E8-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,3-triazol-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(113 mg, 0.28 mmol) in 85% hydrazine monohydrate (4 mL) stirred for 3 hrat room temperature. The mixture was filtered and washed with water,petroleum ether and ethyl acetate to give the crude product, which waspurified by prep-HPLC to give the title compound (41 mg, yield 39%).¹H-NMR (400 MHz, DMSO-d6) □□ δ (ppm): 3.93 (s, 3H), 4.50-4.52 (d, J=7.6Hz, 1H), 4.96-4.98 (d, J=7.6 Hz, 1H), 7.09-7.15 (m, 3H), 7.35-7.42 (m,4H), 7.55-7.57 (t, J=7.6 Hz, 1H), 7.72 (s, 1H); LC-MS (ESI) m/z: 363(M+1)⁺.

Example 101N,N-Dimethyl-4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzamideExample 101A 4-Formyl-N,N-dimethylbenzamide

To a suspension of 4-formylbenzoic acid (4.00 g, 26.7 mmol) in dry DCM(8 mL) were added thionyl chloride (2.92 g, 40.0 mmol) and DMF (0.6 mL)dropwise at ambient temperature under nitrogen. The reaction mixture wasrefluxed for 2 h. After cooling, this mixture was added to 33%dimethylamine in water (10.5 mL, 72 mmol) dropwise over 15 min in anice-water bath, and the reaction mixture stirred for 1 h at the sametemperature. The solvent was evaporated in vacuums. The residue waspurified by chromatography on silica gel to give the title compound (2.5g, yield 53%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86(s, 3H), 3.30 (s, 3H), 7.60 (d, J=7.6 Hz, 2H), 7.95 (d, J=7.6 Hz, 2H),10.04 (s, 1H); LC-MS (ESI) m/z: 178 (M+1)⁺.

Example 101B(E)-N,N-dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4ylimino)methyl)benzamide

4-Aminoisobenzofuran-1(3H)-one (2.10 g, 14.1 mmol),4-formyl-N,N-dimethylbenzamide (2.50 g, 14.1 mmol) and dry MgSO₄ (9.84g, 82 mmol) were added to acetonitrile (170 mL) and stirred under refluxovernight. The mixture was filtered, and the solvent was evaporatedunder reduced pressure and the residue was re-crystallized to obtain 3.5g of title compound as a pale solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm):3.01 (s, 3H), 3.15 (s, 3H), □ 5.43 (s, 2H), 7.38-7.40 (d, J=7.6 Hz, 1H),7.55-7.61 (m, 3H), 7.80-7.82 (d, J=7.6 Hz, 1H), 7.96-7.98 (d, J=8 Hz,2H), 8.58 (s, 1H); LC-MS (ESI) m/z: 308 (M+1)⁺.

Example 101C Ethyl2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

(E)-N,N-Dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4ylimino)methyl)benzamide(924 mg, 3.0 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (363 mg, 3.3mmol), sodium (276 mg, 12 mmol) in ethanol (30 mL) and ethyl propionate(45 mL) were added and the mixture was stirred at room temperatureovernight. Then the resulting mixture was evaporated under reducedpressure and extracted with ethyl acetate (100 mL×4) and concentrated.The crude product was purified by column chromatography (silica gel,petroleum ether/ethyl acetate=20:1 to 1:2) to afford the title compoundas a yellow solid (500 mg, yield 37%). LC-MS (ESI) m/z: 447 (M+1)⁺.

Example 101DN,N-dimethyl-4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzamide

Ethyl2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(500 mg, 1.12 mmol) and hydrazine monohydrate (8 mL) were added and themixture was stirred under 40° C. for 3 h. Then the mixture was cooled toroom temperature and filtered to give the title compound (90 mg, yield19%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86 (s, 3H),2.96 (s, 3H), 3.42 (s, 3H), □4.66-4.69 (d, J=10.4 Hz, 1H), 4.96-4.99 (d,J=10.4 Hz, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.16-7.19 (m, J=7.6 Hz, 1H),7.29-7.45 (m, 6H), 7.56-7.60 (t, J=7.6 Hz 1H), 12.18 (s, 1H); LC-MS(ESI) m/z: 415 (M+1)⁺.

Example 1029-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 102A

Isothiocyanatomethane

To a solution of methylamine hydrochloride (61 g, 0.9 mol) in 100 mL ofwater was added carbon disulfide (68.5 g, 0.9 mol). The mixture wascooled to 10° C., a cold solution of sodium hydroxide (72 g, 1.8 mol) inwater (160 mL) was added dropwise over a period of 30 min. After theaddition, the internal temperature rise to 85° C. gradually. Thesolution was kept at this temperature for 1.5 hr. The bright redsolution was cooled to 35° C.˜40° C., and was added ethylchlorocarbonate (98 g, 0.9 mol) over a period of 1 hr with stirring. Thestirring was continued for 30 min after the addition. The mixture wasallowed to stand overnight. The organic layer was separated, dried overNa₂SO₄, and distilled under atmosphere pressure. The fraction, whichboils at 115˜120° C., was collected as a colorless crystal (40 g, yield61%). ¹H-NMR (400 MHz, CDCl₃) δ (ppm): □3.29 (s, 3H).

Example 102B 2-Acetyl-N-methylhydrazinecarbothioamide

To a stirred solution of acetohydrazide (3.7 g, 50 mmol) in methanol (30mL) was added a solution of compound isothiocyanatomethane (3.65 g, 50mmol) in methanol (50 mL) at 0° C. After the addition, the mixture wasstirred at room temperature overnight. The mixture was concentrated togive crude product (7 g) as a white solid which was used in the nextstep without further purification. LC-MS (ESI) m/z: 148 (M+1)⁺.

Example 102C 3,4-Dimethyl-1H-1,2,4-triazole-5(4H)-thione

To a stirred solution of crude 2-acetyl-N-methylhydrazinecarbothioamide(7 g, 47.6 mmol) in ethanol (100 mL) was added triethylamine (14.4 g,143 mmol). After the addition, the mixture was heated to refluxovernight and was then concentrated to give the title compound (4.2 g,yield 65% for two steps) as a white solid which was used in the nextstep without further purification. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):2.28 (s, 3H), 3.38 (s, 3H), 13.40 (s, 1H). LC-MS (ESI) m/z: 130 (M+1)⁺.

Example 102D 3,4-Dimethyl-4H-1,2,4-triazole

A suspension of 3,4-dimethyl-1H-1,2,4-triazole-5(4H)-thione (4.2 g, 32.5mmol) in dichloromethane (72 mL) was cooled to 0° C. A solution of 30%hydrogen peroxide (16.9 mL, 149.5 mmol) in acetic acid (44 mL) was addeddropwise. After the addition, the mixture was allowed to stir at roomtemperature overnight. The solvent was removed under reduced pressure.The residue was dissolved with water (20 mL), treated with aqueoussodium hydroxide to pH=12, extracted with dichloromethane (80 mL×8). Thecombined organic layers were dried over anhydrous Na₂SO₄, concentratedto give the title compound (2.3 g, yield 73%) as a brown solid. ¹H-NMR(400 MHz, CDCl₃) δ (ppm): □2.47 (s, 3H), 3.63 (s, 3H), 8.09 (s, 1H).LC-MS (ESI) m/z: 98 (M+1)⁺.

Example 102E (4,5-Dimethyl-4H-1,2,4-triazol-3-yl)methanol

A mixture of 3,4-dimethyl-4H-1,2,4-triazole (2.3 g, 23.7 mmol) andformalin (5 mL) was heated to 90° C. overnight. The mixture wasconcentrated to give crude product. The crude product was purified bysilica gel chromatography (dichloromethane/methanol=200:1 to 15:1) togive the title compound (2.48 g, yield 82%) as a white solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): □2.31 (s, 3H), 3.52 (s, 3H), 4.52-4.54 (d,J=5.2 Hz, 2H), 5.49-5.51 (t, J=5.2 Hz, 1H). LC-MS (ESI) m/z: 128 (M+1)⁺.

Example 102F 4,5-Dimethyl-4H-1,2,4-triazole-3-carbaldehyde

A mixture of (4,5-dimethyl-4H-1,2,4-triazol-3-yl)methanol (2.48 g, 19.5mmol) and manganese (IV) oxide (17.8 g, 204.8 mmol) in drytetrahydrofuran (72 mL) was stirred at room temperature overnight. Themixture was filtered, and the cake washed with dichloromethane (100mL×3). The combined filtrate was concentrated to give the title compound(1.6 g, yield 66%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):□2.54 (s, 3H), 3.89 (s, 3H), 10.06 (s, 2H). LC-MS (ESI) m/z: 126 (M+1)⁺.

Example 102G Ethyl3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (237 mg, 1mmol) and 4,5-dimethyl-4H-1,2,4-triazole-3-carbaldehyde (150 mg, 1.2mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol [sodium (92 mg, 4 mmol) in ethanol (5 mL)]was added dropwise. After the addition, the mixture was stirred at 10°C. for 5 hr, then 30° C. 2.5 hr. The mixture was quenched with water (10mL) and solvent was removed in vacuum. The residue was dissolved inwater, and then extracted with ethyl acetate (30 mL×4). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated to give crude product. The crude product waspurified by chromatography (silica gel, petroleum ether/ethylacetate=5:1 then ethyl acetate/methanol=15:1) to give the title compound(60 mg, yield: 15%). LC-MS (ESI) m/z: 391 (M+1)⁺.

Example 102H9-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(60 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) wasstirred at 10° C. for 2.5 h. The mixture was purified by prep-HPLC toobtain the title compound as a yellow solid (6 mg, yield: 11%). ¹H-NMR(400 MHz, CD₃OD) δ (ppm): 2.33 (s, 3H), 3.36 (s, 3H), 4.79-4.81 (d,J=11.6 Hz, 1H), 4.99-5.02 (d, J=11.6 Hz, 1H), 7.21-7.23 (m, 2H),7.31-7.33 (m, 2H), 7.45-7.48 (m, 2H), 7.59-7.67 (m, 2H); LC-MS (ESI)m/z: 359 (M+1)⁺.

Example 1039-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 103A Ethyl3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one(510 mg, 2 mmol) and 4,5-dimethyl-4H-1,2,4-triazole-3-carbaldehyde (275mg, 2.2 mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then asolution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) inethanol (10 mL)) was added dropwise. After the addition, the mixture wasstirred at 10° C. for 2 hr, then 30° C. for 4 hr. The mixture wasquenched with water (10 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(30 mL×4). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give a crude product.The crude product was purified by chromatography (silica gel, petroleumether/ethyl acetate=3:1 then ethyl acetate/methanol=30:1) to afford thetitle compound (170 mg, yield: 21%). LC-MS (ESI) m/z: 409 (M+1)⁺.

Example 103B9-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(170 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) wasstirred at 25° C. for 3 h. The mixture was purified by prep-HPLC toobtain the title compound as a yellow solid (40 mg, yield: 26%). ¹H-NMR(400 MHz, DMSO-d6) □ δ (ppm): 2.23 (s, 3H), 3.38 (s, 3H), 4.78-4.80 (d,J=11.0 Hz, 1H), 4.99-5.02 (d, J=11.0 Hz, 1H), 7.11-7.18 (m, 3H),7.35-7.40 (m, 2H), 7.47-7.51 (m, 2H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.19(s, 1H); LC-MS (ESI) m/z: 377 (M+1)⁺.

Example 1042-Fluoro-N,N-dimethyl-5-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzamideExample 104A 5-(Diethoxymethyl)-2-fluorobenzonitrile

To a stirred solution of 2-fluoro-5-formylbenzonitrile (5.96 g, 40 mmol)in ethanol (5.6 g, 120 mmol) was added ammonium chloride (85.6 mg, 1.6mmol). After the addition, the mixture was cooled to 0° C. and triethylorthoformate (6.52 g, 44 mmol) was added dropwise. After the addition,the mixture was stirred at room temperature overnight. The mixture wasconcentrated, then filtered and the cake washed with ethyl acetate (20mL×2). The filtrate was concentrate to give the title compound (8.8 g,yield 98%) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ (ppm):1.22-1.29 (m, 6H), 3.50-3.70 (m, 4H), 5.50 (s, 1H), 7.19-7.24 (t, J=8.8Hz, 1H), 7.70-7.74 (m, 1H), 7.76-7.78 (dd, J₁=6.4 Hz, J₂=2.4 Hz, 1H).LC-MS (ESI) m/z: 224 (M+1)⁺.

Example 104B 2-Fluoro-5-formylbenzoic acid

A mixture of 5-(diethoxymethyl)-2-fluorobenzonitrile (8.8 g, 39.5 mmol)in 3N aqueous sodium hydroxide (100 mL) was heated to 90° C. and stirredfor 8 hr. Then the mixture was cooled to room temperature and acidifiedwith 3N hydrochloric acid to pH=2, and then extracted with ethyl acetate(200 mL×4). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated to give 2-fluoro-5-formylbenzoic acid (6.6 g, yield99%) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 7.34-7.39 (dd,J₁=10 Hz, J₂=8.4 Hz, 1H), 8.14-8.18 (m, 1H), 8.57-8.59 (dd, J₁=7.2 Hz,J₂=2.4 Hz, 1H), 10.04 (s, 1H). LC-MS (ESI) m/z: 169 (M+1)⁺.

Example 104C 2-Fluoro-5-formyl-N,N-dimethylbenzamide

The solution of 2-fluoro-5-formylbenzoic acid (3 g, 17.8 mmol) inmethylene chloride (10 mL) was added thionyl chloride (2.0 mL, 26.7mmol) slowly at 0° C. Then the cold reaction mixture was heated toreflux for 3 h. The solution was cooled to 0° C., added dimethylamine(40 wt. % solution in water, 5 mL) slowly, and then stirred at roomtemperature for 1 h. The solution was washed with water and brine, theorganic layer was dried with Na₂SO₄ and the solvent was removed to getthe desired product (2.4 g, yield 76%). LC-MS (ESI) m/z: 196 (M+1)⁺

Example 104D(E)-2-fluoro-N,N-dimethyl-5-((1-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)benzamide

A solution of 2-fluoro-5-formyl-N,N-dimethylbenzamide (2.38 g, 12.2mmol), 4-aminoisobenzofuran-1(3H)-one (1.82 g, 12.2 mmol), anhydrousmagnesium sulfate (14.67 g, 122 mmol) in acetonitrile (100 ml) washeated to reflux for 2 days. The solution was filtered and removed invacuum. The crude product was re-crystal with isopropanol to give thetitle compound (1.5 g, yield: 37%) ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):2.91-2.92 (d, J=0.4 Hz, 3H), 3.07 (s, 3H), 5.55 (s, 2H), 7.52-7.56 (t,J=8.8 Hz, 1H), 7.67-7.70 (m, 2H), 7.76-7.78 (m, 1H), 8.02-8.04 (m, 1H),8.10-8.14 (m, 1H), 8.83 (s, 1H); LC-MS (ESI) m/z: 327 (M+1)⁺.

Example 104E Ethyl2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1.0mmol) and(E)-2-fluoro-N,N-dimethyl-5-((1-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)benzamide(300 mg, 0.92 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Thena solution of sodium ethoxide in ethanol (sodium (85 mg, 3.68 mmol) inethanol (5 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 2.5 hr. The mixture was quenched withwater (20 mL) and solvent was removed in vacuum. The residue wasdissolved in water and extracted with ethyl acetate three times, washedby water, brine then the extraction was evaporated, the crude productwas purified by chromatography to obtain a yellow solid. The solid wasdried in vacuum at 50° C. to give the title compound (130 mg, yield:30%). LC-MS (ESI) m/z: 465 (M+1)⁺.

Example 104F2-Fluoro-N,N-dimethyl-5-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzamide

A mixture of compound ethyl2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(130 mg) in hydrazine monohydrate (85%, 2 mL) and methanol (5 mL) wasstirred at room temperature for 4 h. The resulting mixture was filteredand washed with water (20 ml) and methanol (5 ml) to obtain a whitesolid. The solid was dried in vacuum at 50° C. to obtain the titlecompound (30.0 mg, yield 30%). ¹H-NMR (400 MHz, DMSO-d6) □ δ (ppm): 2.72(s, 3H), 2.97 (s, 3H), 3.43 (s, 3H), 4.67-4.70 (d, J=10.8 Hz, 1H),4.95-4.97 (d, J=10.8 Hz, 1H), 6.72-6.73 (d, J=1.2 Hz, 1H), 6.89-6.89 (d,J=0.8 Hz, 1H), 7.15-7.23 (m, 2H), 7.34-7.41 (m, 3H), 7.48-7.49 (m, 1H),7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)⁺.

Example 1058-(4-Chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 105A (E)-4-(4-Chlorobenzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of 4-chlorobenzaldehyde (2.3 g, 16.1 mmol) andanhydrous magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile(200 ml) was added 4-aminoisobenzofuran-1(3H)-one (2 g, 13.4 mmol) atroom temperature. After the addition, the mixture was stirred at refluxfor overnight. The mixture was filtered and the cake was washed withethyl acetate (50 mL×3). The filtrate was concentrated to give crudeproduct. The crude product was washed with petroleum ether andre-crystallized from ethyl acetate to give the title compound (2 g,yield: 55%). LC-MS (ESI) m/z: 272 (M+1)⁺.

Example 105B Ethyl2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(4-chlorobenzylideneamino)isobenzofuran-1(3H)-one(500 mg, 1.85 mmol) and N-methyl-2-imidazolecarbaldehyde (222 mg, 2.1mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol (sodium (174 mg, 7.4 mmol) in ethanol (10mL)) was added dropwise. After the addition, the mixture was stirred atroom temperature for 2 hr. The mixture was quenched with water (10 mL)and solvent was removed in vacuum. The residue was dissolved in water,and then extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=1:1) to givethe title compound (150 mg, yield 20%). LC-MS (ESI) m/z: 410 (M+1)⁺.

Example 105C8-(4-Chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg, 0.37 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6ml) was stirred at room temperature for 2h. The mixture was filtered andwashed with water to give the title compound (89 mg, yield: 65%). ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 3.44 (s, 3H), 4.69 (d, J=10.8 Hz, 1H), 4.96(d, J=10.8 Hz, 1H), 6.76 (s, 1H), 6.93 (d, 1H), 7.16 (d, J=8 Hz, 1H),7.33-7.44 (m, 6H), 7.56-7.60 (m, 1H), 12.19 (d, 1H); LC-MS (ESI) m/z:378 (M+1)⁺.

Example 1069-(1-Methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 106A(E)-4-(4-(Trifluoromethyl)benzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16.1mmol) and anhydrous Magnesium sulfate (16 g, 134 mmol) in anhydrousacetonitrile (200 mL) was added 4-aminoisobenzofuran-1(3H)-one (2 g,13.4 mmol) at room temperature. After the addition, the mixture wasstirred at reflux for overnight. The mixture was filtered and the cakewas washed with ethyl acetate (50 mL×3). The filtrate was concentratedto give crude product. The crude product was washed with petroleum etherand re-crystallized from ethyl acetate to give the title compound (2.8g, yield: 68%). LC-MS (ESI) m/z: 306 (M+1)⁺.

Example 106B Ethyl3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-(trifluoromethyl)benzylideneamino)isobenzofuran-1(3H)-one (1 g,3.28 mmol) and N-methyl-2-imidazolecarbaldehyde (400 mg, 3.61 mmol) inethyl propionate (40 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (31 mg, 13.1 mmol) in ethanol (10 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=1:1) to givethe title compound (150 mg, yield 8%). LC-MS (ESI) m/z: 444 (M+1)⁺.

Example 106C9-(1-Methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg, 0.34 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6mL) was stirred at room temperature for 2h. The mixture was filtered andwashed with water to give the title compound (25 mg, yield: 18%). ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 3.46 (s, 3H), 4.81 (d, J=10.8 Hz, 1H), 5.07(d, J=10.8 Hz, 1H), 6.82 (s, 1H), 6.97 (d, 1H), 7.16 (d, J=8 Hz, 1H),7.41 (d, J=7.6 Hz 2H), 7.58-7.69 (m, 5H), 12.22 (d, 1H); LC-MS (ESI)m/z: 412 (M+1)⁺.

Example 1078-(4-Fluorophenyl)-9-(thiazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 107A

Ethyl2-(4-fluorophenyl)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one(1.88 g, 7.37 mmol) and thiazole-2-carbaldehyde (1 g, 8.8 mmol) in ethylpropionate (50 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (678 g, 29 mmol) in ethanol (30 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 2 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10)to give the crude compound (180 mg). LC-MS (ESI) m/z: 397 (M+1)⁺.

Example 107B8-(4-Fluorophenyl)-9-(thiazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(180 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) wasstirred at 45° C. for overnight. Methanol was removed under reducedpressure. The mixture was filtered and washed with water to give thetitle compound (3 mg, yield: 2%). ¹H-NMR (400 MHz, CD₃OD) □□ δ (ppm):4.88 (d, J=8.0 Hz, 1H), 5.09 (d, J=8.0 Hz, 1H), 7.01 (t, 2H), 7.21 (d,1H), 7.36-7.40 (m, 2H), 7.47 (d, 1H), 7.59 (d, 1H), 7.65 (t, 1H), 7.74(d, 1H); ¹⁹F-NMR (400 MHz, CD₃OD) δ(ppm): −116.36 (s); LC-MS (ESI) m/z:365 (M+1)⁺.

Example 1089-(1-Ethyl-1H-imidazol-2-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 108A Ethyl3-(1-ethyl-1H-imidazol-2-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one(765 mg, 3 mmol) and N-ethyl-2-imidazolecarbaldehyde (372 mg, 3 mmol) inethyl propionate (45 mL) was cooled to 0° C. Then a solution of sodiumethoxide (sodium (276 mg, 12 mmol) in ethanol (45 mL)) was addeddropwise. After the addition, the mixture was stirred at roomtemperature for 4 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate=25:1 to 5:1)to give the title compound (90 mg, yield: 7%). LC-MS (ESI) m/z: 408(M+1)⁺.

Example 108B Synthesis of9-(1-Ethyl-1H-imidazol-2-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(1-ethyl-1H-imidazol-2-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(90 mg, 0.22 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (10mL) was stirred for 4 h at room temperature. Methanol was removed underreduced pressure. The mixture was filtered and washed with water to givethe crude product. The crude product was purified by prep-HPLC to givethe title compound (38.5 mg, yield: 47%). ¹H-NMR (400 MHz, MeOD)□□δ(ppm): 1.06-1.09 (t, J=7.2 Hz, 3H), 3.74-3.78 (m, 2H), 4.60-4.62 (d,J=11.6 Hz, 1H), 4.98-5.01 (d, J=11.6 Hz, 1H), 6.91-7.02 (m, 4H),7.19-7.21 (m, 1H), 7.39-7.43 (m, 2H), 7.56-7.64 (m, 2H); LC-MS (ESI)m/z: 376 (M+1)⁺.

Example 1098-(4-((4-Ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition themixture was stirred at room temperature overnight. Then the mixture wascooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. Afterthe addition, the mixture was stirred at this temperature for 12 hr. DCMwas removed under reduced pressure. The residue was washed with ethylacetate/methanol (10/1) and filtered. The filtrate was concentrated togive the crude product, which was purified by prep-HPLC to give thetitle compound as white solid (90 mg, yield 71%). ¹H-NMR (400 MHz,DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56(m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H),7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS(ESI) m/z: 552 (M+1)⁺.

Example 1108-(4-((4-Ethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 0.52 mmol), N-ethylpiperazine (209 mg, 1.56 mmol) and aceticacid (156 mg, 2.6 mmol) in dichloromethane (30 mL) was stirred at roomtemperature overnight. Then the mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (165 mg, 0.78 mmol) was added. After the addition,the mixture was stirred at room temperature for 5 h. Dichloromethane wasremoved under reduced pressure. The crude product was purified bypre-HPLC to give the title compound (96 mg, yield 33%). ¹H-NMR (400 MHz,CD₃OD) δ (ppm): 1.37-1.41 (t, J=6.8 Hz, 3H), 3.30-3.34 (m, 2H),3.47-3.86 (m, 8H), 4.36-4.38 (d, J=7.6 Hz, 1H), 4.46 (s, 2H), 4.80-4.82(d, J=8.4 Hz, 1H), 6.92-6.96 (m, 2H), 7.11-7.15 (m, 2H), 7.21-7.23 (m,1H), 7.42-7.45 (m, 2H), 7.51-7.56 (m, 3H), 7.63-7.67 (m, 1H). LC-MS(ESI) m/z: 484 (M+H)⁺.

Example 1114-(9-(4-Fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)-N,N-dimethylbenzamideExample 111A Ethyl2-(4-(dimethylcarbamoyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

Compound(E)-N,N-dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)benzamide(1.36 g, 4.4 mmol), 4-fluorobenzaldehyde (600 mg, 4.84 mmol), sodium(405 mg, 17.6 mmol), ethanol (40 mL) and ethyl propionate (66 mL) wereadded and the mixture was stirred at room temperature overnight. Thenthe resulting mixture was evaporated under reduced pressure andextracted with ethyl acetate (100 mL×4) and concentrated. The crudeproduct was purified by column chromatography (silica gel, petroleumether/ethyl acetate=20:1 to 5:1) to give the title compound as a solid(490 mg, yield 22%). LC-MS (ESI) m/z: 461 (M+1)⁺.

Example 111B4-(9-(4-Fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)-N,N-dimethylbenzamide

A mixture of ethyl2-(4-(dimethylcarbamoyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(490 mg, 1 mmol) and hydrazine monohydrate (15 mL) was stirred at 40° C.for 3 h. Then the mixture was cooled to room temperature and filtered togive the title compound (110 mg, yield 24%) as a white solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 2.82 (s, 1H), 2.93 (s, 1H), □4.36-4.38 (d,J=9.2 Hz, 1H), 4.78-4.80 (d, J=9.2 Hz, 1H), 7.01-7.03 (m, 2H), 7.14-7.19(m, 3H), 7.25-7.28 (m, 2H), 7.32-7.40 (m, 3H), 7.45 (s, 1H), 7.56-7.60(t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)⁺.

Example 1124-(8-(4-((Dimethylamino)methyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamideExample 112A Ethyl2-(4-(diethoxymethyl)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a mixture of 4-formyl-N,N-dimethylbenzamide (960 mg, 5.42 mmol),(E)-4-(4-(diethoxymethyl)benzylideneamino) isobenzofuran-1(3H)-one (1.84g, 5.42 mmol) and sodium methoxide (499 mg, 21.7 mmol) was added toethyl propionate (30 mL) and the mixture was stirred at room temperatureovernight. Then the resulting mixture was evaporated under reducedpressure and extracted with EtOAc (100 mL×4) and concentrated. This gavethe crude product (250 mg). LC-MS (ESI) m/z: 545 (M+1)⁺.

Example 112B4-(8-(4-(Diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide

Ethyl2-(4-(diethoxymethyl)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(250 mg, 0.46 mmol) and hydrazine monohydrate (85%, 5 mL) were added inMeOH (15 mL) and the mixture was stirred room temperature for 5 h. Theresulting mixture was concentrated under reduced pressure to a volume of15 mL and then filtered; the filtrate was evaporated to give the titlecompound as a white solid (180 mg, yield 76%). LC-MS (ESI) m/z: 513(M+1)⁺.

Example 112C4-(8-(4-Formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide

To a solution of4-(8-(4-(diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide(180 mg, 0.35 mmol) in acetonitrile (10 mL) was added trifluoroaceticacid (5 mL), stirred for 30 min, Then the mixture was evaporated underreduced pressure to get the title compound (140 mg, yield 91%). LC-MS(ESI) m/z: 439 (M+1)⁺.

Example 112D4-(8-(4-((Dimethylamino)methyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide

To a stirred solution of4-(8-(4-formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide(140 mg, 0.32 mmol) in dried DCM (20 mL) was added acetic acid followedby dimethylamine (57 mg, 1.3 mmol). After the addition, the mixture wasstirred at room temperature overnight. Then the mixture was cooled to 0°C. Sodium borohydride (102 mg, 0.48 mmol) was added. After the addition,the mixture was stirred at this temperature for 12 hr. DCM was removedunder reduced pressure. The residue was washed with ethylacetate/methanol (10/1) and filtered. The filtrate was concentrated togive the crude product, which was purified by prep-HPLC to give thetitle compound as a white solid (15 mg, yield 10%). ¹H-NMR (400 MHz,CD₃OD) δ (ppm): 2.19 (dd, 6H), 2.93 (s, 3H), 3.06 (s, 3H), 3.40 (dd,2H), 4.34 (d, 1H), 4.16-7.19 (m, 5H), 7.23-7.26 (m, 4H), 7.54 (d, 1H),7.61 (t, 1H). LC-MS (ESI) m/z: 468 (M+1)⁺.

Example 1139-(4-Fluorophenyl)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(150 mg, 0.39 mmol), N-methylpiperazine (117 mg, 1.17 mmol) and aceticacid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at roomtemperature overnight. Then the mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition,the mixture was stirred at room temperature for 5 h. Dichloromethane wasremoved under reduced pressure. The crude product was purified byprep-HPLC to give the title compound (48 mg, yield 22%). ¹H-NMR (400MHz, CD₃OD) δ (ppm): 3.02 (s, 3H), 3.60-3.81 (m, 8H), 4.36-4.38 (d,J=7.6 Hz, 1H), 4.47 (s, 2H), 4.80-4.82 (d, J=7.6 Hz, 1H), 6.93-6.97 (m,2H), 7.12-7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.43-7.45 (m, 2H), 7.52-7.57(m, 3H), 7.64-7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)⁺.

Example 1149-(4-Fluorophenyl)-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 114A tert-Butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)piperazine-1-carboxylate

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(150 mg, 0.39 mmol), tert-butyl piperazine-1-carboxylate (218 mg, 1.17mmol), and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL)was stirred at room temperature overnight. Then the mixture was cooledto 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added.After the addition, the mixture was stirred at room temperature for 5 h.Dichloromethane was removed under reduced pressure. The crude productwas purified by flash chromatography to give the title compound (70 mg,yield 32%). LC-MS (ESI) m/z: 556 (M+1)⁺.

Example 114B9-(4-Fluorophenyl)-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

The mixture of tert-butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)piperazine-1-carboxylate(70 mg, 0.12 mmol) in a solution of HCl(g) in acetonitrile (sat. 10 mL)was stirred for 3 hr at room temperature. Then the mixture was filteredto give the crude product. The crude product was purified by flashchromatography to give the title compound as a hydrochloride salt (35mg, yield 60%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.63-2.64 (m, 4H),3.19-3.21 (m, 4H), 3.54 (s, 2H), 4.29-4.31 (d, J=8.0 Hz, 1H), 4.69-4.71(d, J=8.4 Hz, 1H), 6.89-6.93 (m, 2H), 7.07-7.10 (m, 2H), 7.19-7.26 (m,5H), 7.54-7.56 (m, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 456 (M+1)⁺.

Example 1159-(4-fluorophenyl)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 115A 4-Benzyl 1-tert-butyl 2-methylpiperazine-1,4-dicarboxylate

To the solution of 2-methyl-piperazine (2.0 g, 20 mmol) in methylenechloride (15 mL) at 0° C. was added benzylchloroformate (3.0 mL)dropwise. The mixture was stirred at 0° C. for 1 hr and then at roomtemperature for 2 hr. The mixture was then cooled to 0° C., anddiisopropylethylamine (4.5 mL) was added and followed by (Boc)₂O (4.8 g,22 mmol). The mixture was stirred at room temperature overnight, andthen the solvent was removed by rotary evaporation. The residue wasdissolved in EtOAc, washed with water and brine, dried over Na₂SO₄, andpurified with column chromatograph on silica gel (EtOAc:hexane=1:9) togive an oily intermediate (4.8 g, 72%). LC-MS (ESI) m/z: 357 (M+23)⁺.

Example 115B tert-Butyl 2-methylpiperazine-1-carboxylate

A solution of 4-benzyl 1-tert-butyl 2-methylpiperazine-1,4-dicarboxylate(4.8 g, 14.4 mmol) in methanol (25 mL) was added 480 mg of 10% Pd/C andstirred at room temperature under hydrogen overnight. Filtered andconcentrated to give the title product (2.8 g, yield 97%) as colorlessoil. ¹H-NMR (400 MHz, CDCl₃) □□δ (ppm): 1.21 (d, J=6.8 Hz, 3H), 1.46 (s,9H), 2.64-2.70 (m, 1H), 2.74-2.78 (m, 1H), 2.88-3.01 (m, 3H), 3.78 (d,J=12.4 Hz, 1H), 4.16 (m, 1H); LC-MS (ESI) m/z: 201 (M+1)⁺.

Example 115C tert-Butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2-methylpiperazine-1-carboxylate

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 0.52 mmol) and tert-butyl 2-methylpiperazine-1-carboxylate (311mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at roomtemperature overnight, then NaBH₃CN (129 mg, 2.1 mmol) was added and themixture was stirred for another 5 hours. Concentrated and the residuewas purified by chromatography (silica gel, petroleum ether/ethylacetate=3:1 to 1:1) to give the title compound (70 mg, yield 24%). LC-MS(ESI) m/z: 570 (M+1)⁺.

Example 115D9-(4-Fluorophenyl)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of tert-butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2-methylpiperazine-1-carboxylate(70 mg, 0.123 mole) in 2 ml of HCl-acetonitrile was stirred for 2 hours.Concentrated and the residue was purified by prep-HPLC to afford thetitle produce as a white solid (30 mg, yield 52%). ¹H-NMR (400 MHz,DMSO-d6) □□δ (ppm): 0.87 (d, J=6.4 Hz, 3H), 1.49 (t, J=10 Hz, 1H), 1.83(t, J=10 Hz, 1H), 2.55 (m, 2H), 2.64 (m, 2H), 2.75 (m, 1H), 3.32 (s,3H), 4.34 (d, J=9.2 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 6.97-7.01 (m, 2H),7.13-7.24 (m, 7H), 7.37-7.41 (m, 2H), 7.55-7.59 (m, 1H), 12.15 (s, 1H);LC-MS (ESI) m/z: 470 (M+1)⁺.

Example 1164-(8-(4-Fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamideExample 116A Ethyl3-(4-(dimethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

Sodium (115 mg, 5 mmol) was added to EtOH (10 mL) to afford sodiumethoxide. (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (500mg, 1.96 mmol) and 4-formyl-N,N-dimethylbenzamide (382 mg, 2.16 mmol)were dissolved in ethyl propionate (10 mL), and the sodium ethoxidesolution was added dropwise to the mixture at 0° C., then the mixturewere heated to 30° C. for 1 h. To the reaction mixture was added waterand EtOAc, the organic phase was separated, washed with water and brine.The organic phase was dried over anhydrous sodium sulfate and thenconcentrated to afford the crude product. The crude product was purifiedby flash chromatography (MeOH:DCM 1:25) to give the title compound (400mg, yield 44%). LC-MS (ESI) m/z: 461 (M+1)⁺

Example 116B4-(8-(4-Fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide

A mixture of ethyl3-(4-(dimethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(400 mg, 0.87 mmol) and hydrazine monohydrate (85%, 10 mL) weredissolved in MeOH (20 mL), and stirred at 35° C. for 2 h. The mixturewas concentrated under reduced pressure. The resulting mixture wasfiltered, the solid was washed with water and methanol to obtain a whitesolid, and the solid was dried in vacuum at 40° C. to obtain the titlecompound (100 mg, yield 54%). ¹H-NMR (400 MHz, DMSO-d6) □□ δ (ppm): 2.85(s, 3H), 2.94 (s, 3H), 4.37-4.40 (d, 1H), 4.80-4.82 (d, 1H), 7.17-7.25(m, 5H), 7.33-7.36 (m, 2H), 7.39-7.41 (d, 1H), 7.45 (s, 1H), 7.57-7.61(t, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)⁺.

Example 1179-(4-Fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 117A9-(4-Fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(0.1 g, 0.26 mmol) in anhydrous DCM (4 mL) was added AcOH (94 mg, 1.56mmol) at 25° C. for 0.5 h, then pyrrolidine (37 mg, 0.52 mmol) was addedat 25° C., stirred overnight. NaBH(OAc)₃ was added at ice bath, andstirred for 5 h. The mixture was concentrated to give the crude product.The crude product was dissolved in ethyl acetate and to this solutionwas added 2N HCl (10 mL). The aqueous phase was separated and 20% NaOH(20 ml) was added. The mixture was extracted with ethyl acetate and theorganic phase was separated to give the title compound (30 mg, yield26%). LC-MS (ESI) m/z: 441 (M+1)⁺.

Example 117B9-(4-Fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of9-(4-fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(30 mg) in HCl/methanol solution (20 mL) was stirred at 25° C. for 0.5h. Methanol was removed under reduced pressure. The mixture was filteredand washed with water, dried overnight at 50° C. to give the titlecompound (24 mg, yield 74%). ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.00 (s,2H), 2.16 (s, 2H), 3.14 (s, 2H), 3.41 (s, 2H), 4.32 (s, 2H), 4.35-4.38(d, 1H), 4.78-4.80 (d, 1H), 6.91-6.95 (t, 2H), 7.10-7.13 (t, 2H),7.22-7.24 (d, 1H), 7.42 (m, 4H), 7.56-7.58 (d, 2H), 7.64-7.70 (1H);LC-MS (ESI) m/z: 441 (M+1)⁺.

Example 118 9-Phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 118A2-Oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide

To a solution of 4-aminoisobenzofuran-1(3H)-one (4.0 g, 26.8 mmol),2-oxo-2-phenylacetic acid (4.1 g, 26.8 mmol), and HBTU (15.2 g, 40.2mmol) in dichloromethane (240 mL) was added TEA (8 mL). The reactionmixture was stirred at room temperature overnight. The resulting mixturewas added water and adjusted to pH=6-7 with 1% aq. HCl, and then wasfiltered. The filtrate was extracted with ethyl acetate. The ethylacetate layer was evaporated and the crude product was purified bygradient chromatography (silica gel, petroleum ether/ethyl acetate 6:1to 3:1) to give the title compound (5.0 g, yield 66%). LC-MS (ESI) m/z:282 (M+1)⁺.

Example 118BN-(4-Methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide

To a solution of2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (5 g,11.7 mmol) in DMF (48 mL) was added NaH (0.78 g, 19.5 mmol). Thesolution was stirring at room temperature for 1.5 hr, followed by theaddition of 1-(chloromethyl)-4-methoxy-benzene (2.8 mL). After stirredat 30° C. overnight, the resulting mixture was added water and adjustedto pH=3-4 with 0.5 N aq. HCl. Then ethyl acetate was added, concentratedand filtered, the filtrate was washed by ethyl acetate, the combineethyl acetate layer was washed with brine, dried over anhydrous sodiumsulfate, concentrated, and purified by flash chromatography on silicagel to obtain the desired compound (4.7 g, yield 66%). LC-MS (ESI) m/z:402 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) □□ δ (ppm): 3.73 (s, 3H),4.83-5.17 (m, 4H), 6.89-6.91 (d, J=8.8 Hz, 2H), 7.18-7.20 (m, 2H),7.24-7.26 (m, 1H), 7.38-7.42 (t, 1H), 7.52-7.56 (m, 2H), 7.69-7.71 (m,1H), 7.75-7.81 (m, 3H).

Example 118C Ethyl4-hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate

A mixture ofN-(4-methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide(4.7 g, 11.7 mmol) and anhydrous Na₂SO₄ (16.6 g, 117 mmol) in anhydrousethyl propionate (120 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (673 mg, 29.2 mmol) in anhydrous ethanol (70mL)) was added dropwise. After the addition, the mixture was stirred atroom temperature for 18 hr. The mixture was quenched with water (100 mL)and solvent was removed in vacuum. The residue was dissolved in water,and then extracted with ethyl acetate (250 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give product (4.02 g, yield 80%). LC-MS (ESI) m/z: 430(M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) □□δ (ppm): 1.23-1.26 (t, J=6.8 Hz,3H), 3.69 (s, 3H), 4.21-4.23 (m, 2H), 5.46 (s, 1H), 6.86-6.88 (d, J=7.6Hz, 2H), 7.11-7.18 (m, 3H), 7.36-7.55 (m, 7H), 10.59 (s, 1H).

Example 118D Ethyl4-hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate

A mixture of ethyl4-hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate(298 mg, 2 mmol) in trifluoroacetic acid was heated to reflux for 48 h.After the removal of the solvents, the residue was washed by ethylacetate to obtain the title compound as a white solid (250 mg, yield32%). LC-MS (ESI) m/z: 310 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):1.25 (t, J=7.2 Hz, 3H), 4.23 (q, J=7.2 Hz, 2H), 7.08 (d, J=7.2 Hz, 1H),7.31-7.43 (m, 6H), 7.52 (t, J=8 Hz, 1H), 10.39 (s, 1H), 11.64 (s, 1H).

Example 118E 9-Phenyl-2H-pyrido[4,3,2-de]phthalazine-3,8(7H,9H)-dione

Ethyl 4-hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate (330mg, 1.1 mmol) was added to hydrazine monohydrate (1 mL) and methanol (2mL), the mixture was stirred at 110° C. for 2.5 h by microwave. Then themixture was cooled to room temperature, the solvent was evaporated invacuum. The residue was washed with methanol, and then purified bycolumn chromatography (silica gel, dichloromethane/methanol=300:1 to50:1) to obtain a pale white solid (148 mg, yield 53%). LC-MS (ESI) m/z:278 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 5.09 (s, 1H), 7.17-7.40(m, 6H), 7.77-7.81 (m, 2H), 11.10 (s, 1H), 12.57 (s, 1H).

Example 118F9-Phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of 9-phenyl-2H-pyrido[4,3,2-de]phthalazine-3,8(7H,9H)-dione(80 mg, 2.2 mmol), BH₃ (0.7 mL, 1 mol/L in THF), dioxane (4 mL) insealed tube was stirred for 2 h at 95° C. under nitrogen atmosphere.Then the mixture was treated with MeOH˜HCl (g) (0.2 mL), stirred for 20min at 95° C. Then the mixture was cooled and adjusted to pH=8 withEt₃N. The solvent was removed under vacuum and the crude was purified bycolumn chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to1:1) to obtain the title compound as a yellow solid (18.3 mg, yield24%). LC-MS (ESI) m/z: 264 (M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ (ppm):3.60-3.64 (m, 1H), 3.68-3.72 (m, 1H), 4.21 (t, J=5.2 Hz, 1H), □7.09-7.11(d, J=8 Hz, 1H), 7.16-7.29 (m, 5H), 7.53-7.61 (m, 2H).

Example 1198-(4-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 119A Ethyl2-(4-fluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound(E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (690 mg, 2.7mmol) and 4-methyl-4H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.7 mmol)in ethyl propionate (20 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol [sodium (250 mg, 10.8 mmol) in ethanol (10mL)] was added dropwise. After the addition the mixture was stirred atroom temperature for 2.5 hr, then was quenched with water (20 mL) andsolvent was removed in vacuum. The residue was dissolved in water andextracted with ethyl acetate three times, washed with water and brine,and then evaporated to give the crude product, which was purified bychromatography to obtain a yellow solid (120 mg, yield 11%). LC-MS (ESI)m/z: 395 (M+1)⁺.

Example 119B8-(4-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-fluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (5 mL) wasstirred at room temperature for 4 h. Then the solution was evaporated,the crude product was purified by prep-HPLC to obtain the title compoundas a white solid (20 mg, yield 18%). LC-MS (ESI) m/z: 363 (M+1)⁺. ¹H-NMR(400 MHz, DMSO-d6) □ δ (ppm): 3.50 (s, 3H), 4.83-4.86 (d, J=11.6 Hz,1H), 5.00-5.03 (d, J=11.6 Hz, 1H), 7.12-7.19 (m, 3H), 7.39-7.42 (m, 2H),7.47-7.51 (m, 2H), 7.60-7.64 (t, J=8 Hz, 1H), 8.31 (s, 1H), 12.24 (s,1H).

Example 1208-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 120A Ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of 4-(4-fluorobenzylideneamino) isobenzofuran-1(3H)-one(5.0 g, 19.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (2.8 g,25.5 mmol) in ethyl propionate (310 mL) was added sodium ethoxide (1.26g, 54.9 mmol) at room temperature under nitrogen. The mixture wasstirred at 55° C. for 2 hr. Then the resulting mixture was evaporatedunder reduced pressure and extracted with ethyl acetate (150 mL×4) andconcentrated the extracts. The crude product was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate=20:1 to1.5:1). A solid product was obtained (2.4 g, yield 31%). LC-MS (ESI)m/z: 395 (M+1)⁺.

Example 120B8-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A 100 mL round-bottom flask equipped with a thermometer and mageneticstirrer was charged with ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(1.72 g, 4.4 mmol), methanol (15 mL), and NH₂NH₂ (4 mL, 85%). Themixture was stirred at 25° C. for 5 hr. The reaction was monitored byHPLC for completion. The mixture was evaporated under reduced pressureand methanol was added to make slurry. The suspension was filtered. Theobtained solid was washed with 20 mL of methanol, and was dried toafford the title compound (1.4 g, yield 90%). LC-MS (ESI) m/z: 363(M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□ δ (ppm): 3.65 (s, 3H), 4.93-4.97(m, 2H), 7.12-7.19 (m, 3H), 7.39-7.43 (m, 2H), 7.47-7.50 (m, 2H),7.58-7.60 (m, 1H), 7.79 (s, 1H), 12.22 (s, 3H).

Example 1218-(4-Fluorophenyl)-9-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 121A N-Methyl-3-nitropyridin-4-amine

To a suspension of 4-chloro-3-nitropyridine (2 g, 12.6 mmol) indichloromethane (15 mL) was cautiously added methyl amine (25% solutionin water, 10 mL, 63 mmol). The reaction mixture was heated to 40° C.After stirring for 1 h, the mixture was poured into water (20 mL), andthe precipitate was collected by filtration and dried in vacuo to affordthe title compound (1.9 g, yield 98%) as a yellow solid. LC-MS (ESI)m/z: 154 (M+1)⁺.

Example 121B N-4-methylpyridine-3,4-diamine

The suspension of N-methyl-3-nitropyridin-4-amine (2.5 g, 16.3 mmol) andPd/C (10%, 500 mg) in methanol (50 mL) was hydrogenated at roomtemperature overnight. Then the mixture was filtered and the filtratewas evaporated to give the product (1.2 g, yield 60%). LC-MS (ESI) m/z:124 (M+1)⁺

Example 121C 1,2-Dimethyl-1H-imidazo[4,5-c]pyridine

The solution of N4-methylpyridine-3,4-diamine (2.5 g, 20.3 mmol) inacetic anhydride (25 mL) was refluxed overnight. Then acetic anhydridewas evaporated under reduced pressure and 1 N hydrochloride acid wasadded. Then the mixture was extracted with dichloromethane (50 mL×3).The aqueous layer was neutralized with sodium bicarbonate, and extractedwith dichloromethane (50 mL×3). The organic layers were concentrated togive the title compound (1.9 g, yield 64%). LC-MS (ESI) m/z: 148 (M+1)⁺.¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.64 (s, 3H), 3.74 (s, 3H), 7.23-7.24(d, J=5.2 Hz, 1H), 8.39-8.41 (d, J=5.2 Hz, 1H), 8.98 (s, 1H).

Example 121D 1-Methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde

To a solution of 1,2-dimethyl-1H-imidazo[4,5-c]pyridine (500 mg, 3.40mmol) in dry 1,4-dioxane (7.5 mL) wasaddedhttp://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure._structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3 selenium dioxide (665 mg, 5.10 mmol). The mixture heated by microwaveat 130° C. for 5 min. Then the mixture was filtered and concentrated togive the crude product, which was purified by column chromatography(silica gel, petroleum ether:DCM 10:1 to 1:1) to give the title compound(400 mg, yield 28%). LC-MS (ESI) m/z: 162 (M+1)⁺. ¹H-NMR (400 MHz,CD₃OD) δ (ppm): 3.61 (s, 3H), 5.91 (s, 1H), 7.67-7.70 (d, J=5.6 Hz, 1H),8.39-8.41 (d, J=5.6 Hz, 1H), 8.93 (s, 1H).

Example 121E Ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of 1-methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde (400mg, 2.48 mmol), (E)-4-(4-fluorobenzydeneamino) isobenzofuran-1(3H)-one(634 mg, 2.48 mmol) in ethyl propionate (20 ml) were added a solution ofsodium ethanoxide in ethanol [sodium (171 mg, 7.45 mmol) in ethanol (10mL)] at 0° C. Then the mixture was stirred at room temperatureovernight. Then the mixture was quenched with water (10 mL) and solventwas removed in vacuum. The residue was extracted with ethyl acetate (100mL×4). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, and concentrated to give crude product, whichwas purified by chromatography (silica gel, petroleum ether/ethylacetate=25:1 to 5:1) to give the title compound (150 mg, yield 14%).LC-MS (ESI) m/z: 445 (M+1)⁺.

Example 121F8-(4-Fluorophenyl)-9-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

The mixture of ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg, 0.34 mmol) and hydrazine monohydrate (2 mL) in methanol (5 mL)was stirred at room temperature for 4 h. Then methanol was evaporatedunder reduced pressure and the residue was extracted with ethyl acetate(20 mL×4). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated to give crude product,which was purified by chromatography (silica gel, DCM/MeOH=25:1 to 1:1)to give the title compound (6.7 mg, yield 5%). LC-MS (ESI) m/z: 413(M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 3.58 (s, 3H), 4.93-4.95 (d,J=11.6 Hz, 1H), 5.04-5.07 (d, J=11.6 Hz, 1H), 6.85-6.90 (t, J=8.8 Hz,2H), 7.12-7.14 (d, J=8.0 Hz, 1H), 7.38-7.44 (m, 3H), 7.49-7.57 (m, 2H),8.19-8.21 (d, J=5.6 Hz, 1H), 8.72 (s, 1H).

Example 1225-Chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 122A 5-Chloro-2-methyl-3-nitrobenzoic acid

To a conc. H₂SO₄ (90 mL) was added portionwise 5-chloro-2-methylbenzoicacid (13.2 g, 77.6 mmol) at −5˜0° C. Then a mixture of conc. HNO₃(10.5g, 1744 mmol) in conc. H₂SO₄ (15 mL) was added dropwise at −5˜0° C. overa period of about 1.5 hr. After the addition, the mixture was stirred atthis temperature for 2 hr. The mixture was poured into crashed ice withvigorous stirring and the precipitate was collected by filtration. Theprecipitate was dissolved in EtOAc, washed with brine, dried overanhydrous Na₂SO₄, and concentrated to give a crude title compound (13.2g), which was used in the next step without further purification.

Example 122B Methyl 5-chloro-2-methyl-3-nitrobenzoate

A solution of crude 5-chloro-2-methyl-3-nitrobenzoic acid (13.2 g) indry methanol (100 mL) was cooled to 0° C. (3 mL) was added conc. H₂SO₄dropwise. After the addition, the mixture was heated to reflux for 16hr. After removal of solvents under reduced pressure, the crude productwas purified by silica gel chromatography (petroleum ether to petroleumether/EtOAc=50:1) to give the title compound (6.3 g, yield 35% for twosteps) as a white solid. LC-MS (ESI) m/z: 230 (M+1)⁺, 231 (M+2)⁺. ¹H-NMR(400 MHz, CDCl₃) □□ δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.84-7.85 (d,1H), 7.98-7.99 (d, 1H).

Example 122C Methyl 2-(bromomethyl)-5-chloro-3-nitrobenzoate

A mixture of methyl 5-chloro-2-methyl-3-nitrobenzoate (6 g, 26.2 mmol),NBS (5.1 g, 28.8 mmol), and BPO (0.63 g, 2.6 mmol) in CCl₄ (50 mL) washeated to reflux overnight. Water (200 mL) was added and CCl₄ wasremoved under reduced pressure. The residue was extracted with DCM (200mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give crude title compound (7 g, yield 87%)as a brown oil which was used in the next step without purification.

Example 122D 6-Chloro-4-nitroisobenzofuran-1(3H)-one

A mixture of methyl 2-(bromomethyl)-5-chloro-3-nitrobenzoate (7 g, 22.8mmol) in 1, 4-dioxane (50 mL) and water (50 mL) was heated to reflux for4 days. Dioxane was removed under reduced pressure. The residue wasextracted with EtOAc (300 mL×4). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give crude product,which was purified by silica gel chromatography (petroleum ether topetroleum ether/EtOAc=5:1) to give the title compound (4 g, yield 82%)as a white solid.

Example 122E 4-Amino-6-chloroisobenzofuran-1(3H)-one

A suspension of 6-chloro-4-nitroisobenzofuran-1(3H)-one (5 g, 23.5 mmol)and Pd/C (10%, 500 mg) in EtOAc (250 mL) was stirred at 25° C. under 1atm of hydrogen for 12 hr. The mixture was filtered, and the cake waswashed with EtOAc (100 mL×3). The filtrate was concentrated to give thetitle compound (3.87 g, yield 90%) as a white solid. LC-MS (ESI) m/z:184 (M+1)⁺.

Example 122F (E)-4-(Benzylideneamino)-6-chloroisobenzofuran-1(3H)-one

A mixture of 4-amino-6-chloroisobenzofuran-1(3H)-one (1 g, 5.46 mmol),benzaldehyde (0.72 g, 6.79 mmol) and magnesium sulfate (6 g) indichloromethane (80 mL) was stirred at reflux overnight. The mixture wasevaporated under reduced pressure and the residue was dried in vacuum. Acrude product was obtained (740 mg) and used in next step withoutfurther purification.

Example 122G Ethyl7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(benzylideneamino)-6-chloroisobenzofuran-1(3H)-one (720 mg, 2.66mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (330 mg, 3 mmol) in ethylpropionate (40 mL) was added sodium ethoxide (650 mg, 9.6 mmol). Themixture was stirred at room temperature for 3 hr. Then the resultingmixture was evaporated under reduced pressure and extracted with ethylacetate (100 mL×4) and concentrated. The crude product was purified bycolumn chromatography (silica gel, petroleum ether:ethyl acetate=20:1 to1.5:1) to give the title compound as a solid (170 mg, yield 15%).

Example 122H5-Chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(429 mg, 1.05 mmol) in methanol (15 mL) was added hydrazine monohydrate(2 mL). The mixture was stirred at 25° C. for 5 hr. The resultingmixture was concentrated under reduced pressure to a volume of 10 ml andthen filtered, giving 58 mg of solid (yield 14%). LC-MS (ESI) m/z: 378(M+1)⁺; 379 (M+2)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□ δ (ppm): 3.42 (s, 3H),4.69 (d, J=10.0 Hz, 1H), 4.98 (d, J=10.4 Hz, 1H), 5.76 (s, 1H), 6.73 (s,1H), 6.89 (s, 1H), 7.14 (s, 1H), 7.27 (dd, 4H), 7.38 (d, J=6.4 Hz, 2H),7.62 (s, 1H), 12.36 (s, 1H).

Example 1238-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 123A(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one

To a stirred mixture of 4-((dimethylamino)methyl)benzaldehyde (4 g, 24.5mmol) and anhydrous magnesium sulfate (15.8 g, 111.5 mmol) in anhydrousacetonitrile (100 mL) was added 4-amino-6-fluoroisobenzofuran-1(3H)-one(4 g, 22.3 mmol) at 0° C. After the addition, the mixture was stirred atreflux for 3 days. The mixture was filtered and the cake was washed withethyl acetate (50 mL×3). The filtrate was concentrated to give crudeproduct, which was re-crystallized with isopropanol to give the titlecompound (3.7 g, yield 55%). LC-MS (ESI) m/z: 314 (M+1)⁺.

Example 123B Ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one(500 mg, 1.6 mmol) and 4-fluorobenzaldehyde (218 mg, 1.76 mmol) in ethylpropionate (10 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (110 mg, 4.8 mmol) in ethanol (5 mL)) wasadded dropwise. After the addition the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product, which was purified by chromatography(silica gel, petroleum ether/ethyl acetate=1:1) to give the titlecompound (100 mg, yield 13%). LC-MS (ESI) m/z: 465 (M+1)⁺.

Example 123C8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(100 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol (2 mL) wasstirred at room temperature overnight. Methanol was removed underreduced pressure. The crude was purified by prep-HPLC to give the titlecompound (35 mg, yield 37%). LC-MS (ESI) m/z: 433 (M+1)⁺. ¹H-NMR (400MHz, CD₃OD) □□ δ (ppm): 2.12 (s, 3H), 3.35 (s, 2H), 4.21 (d, J=8.0 Hz,1H), 4.64 (d, J=8.0 Hz, 1H), 6.81-6.85 (m, 3H), 6.99-7.01 (m, 2H),7.13-7.19 (m, 5H); ¹⁹F-NMR (400 MHz, CD₃OD) δ (ppm): −105.66 (s),−118.17 (s).

Example 1248,9-Bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 124A Ethyl2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one(1 g, 31.9 mmol) and 4-((dimethylamino) methyl) benzaldehyde (0.52 g,31.9 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then asolution of sodium ethoxide in ethanol (sodium (220 mg, 95.8 mmol) inethanol (20 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 2 hr. The mixture was quenched withwater (10 mL) and solvent was removed in vacuum. The residue wasdissolved in water, and then extracted with ethyl acetate (100 mL×4).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated to give crude product, which waspurified by chromatography (silica gel, dichloromethane/methanol=10:1 to20:3) to give the title (520 mg, yield 33%). LC-MS (ESI) m/z: 503.

Example 124B8,9-Bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(520 mg) in 85% hydrazine monohydrate (10 mL) and methanol (50 mL) wasstirred at 23° C. for overnight. Methanol was removed under reducedpressure. The mixture was filtered and washed with water to give thetitle compound (11 mg, yield 20%). LC-MS (ESI) m/z: 472 (M+1)⁺. ¹H-NMR(400 MHz, CD₃OD) □□ δ (ppm): 2.09 (s, 12H), 3.31 (s, 4H), 4.22 (d, J=8.0Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.80 (dd, 1H), 6.97-6.99 (m, 2H),7.06-7.11 (m, 5H), 7.14-7.16 (m, 2H); ¹⁹F-NMR (400 MHz, CD₃OD) δ (ppm):−105.58 (s).

Example 1258-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 125A 4-(Diethoxymethyl)benzaldehyde

A mixture of terephthalaldehyde (10 g, 74.55 mmol), ammonium chloride(160 mg, 3.0 mmol) in ethanol (10.3 g, 223.6 mmol) was added dropwisetriethoxymethane (12.15 g, 82 mmol) at 0° C. After the addition, themixture was stirred at room temperature overnight. The mixture wasconcentrated, the residue was purified by silica gel chromatography togive the title compound (7.0 g, yield 50%) as a white solid. LC-MS (ESI)m/z: 209 (M+1)⁺.

Example 125B 1-(4-(Diethoxymethyl)phenyl)-N,N-dimethylmethanamine

A solution of 4-(diethoxymethyl)benzaldehyde (6.8 g, 32.69 mmol) anddimethylamine 33 wt. % solution in water (9.25 g, 98 mmol) in methanol(200 mL) was stirred at room temperature for overnight. Sodiumborohydride (1.85 g, 49 mmol) was added by portions with ice cooling.After the addition, the mixture was stirred at room temperature for 4hr. The mixture was quenched with water (100 mL) and extracted withethyl acetate (100 ml×3). The extract was dried over anhydrous sodiumsulfate and concentrated to give crude title compound (7.0 g, yield90%), which was used in the next step without further purification.LC-MS (ESI) m/z: 238 (M+1)⁺.

Example 125C 4-((Dimethylamino)methyl)benzaldehyde

To the mixture of 1-(4-(diethoxymethyl)phenyl)-N,N-dimethylmethanamine(7.0 g, 29.5 mmol) in hydrogen chloride (3M in water 30 mL) was stirredat room temperature for 5 hr. Then the mixture was extracted with ethylacetate (50 ml×3).The aqueous layer was basified with sodium carbonateto pH=10, extracted with ethyl acetate (50 ml×3), dried with anhydroussodium sulfate, and concentrated to give crude product (3.95 g, yield82%). LC-MS (ESI) m/z: 164 (M+1)⁺.

Example 125D(E)-4-(4-((Dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one

A solution of 4-((dimethylamino)methyl)benzaldehyde (1.0 g, 6.13 mmol),4-amino-6-fluoroisobenzofuran-1(3H)-one (1.024 g, 6.13 mmol) andanhydrous magnesium sulfate (7.356 g, 61.3 mmol) in acetonitrile (50 ml)was heated at reflux for 2 days. The solution was filtered andconcentrated in vacuum. The crude product was re-crystallized withisopropanol to obtain the title compound (1.15 g, yield 60%). LC-MS(ESI) m/z: 313 (M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 2.28 (s, 6H),3.52 (s, 2H), 5.38-5.38 (m, 2H), 7.09-7.12 (m, 1H), 7.42-7.44 (m, 1H),7.46-7.48 (d, J=8 Hz, 2H), 7.87-7.89 (d, J=8 Hz, 2H), 8.51 (s, 1H).

Example 125E Ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound benzaldehyde (75 mg, 0.705 mmol) and(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one(220 mg, 0.705 mmol) in ethyl propionate (5 mL) was cooled to 0° C. Thena solution of sodium ethoxide in ethanol (sodium (65 mg, 2.82 mmol) inethanol (3 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 2.5 hr. The mixture was quenched withwater (20 mL) and solvent was removed in vacuum. The residue wasdissolved in water and extracted with ethyl acetate for three times. Theextract was washed with water and brine and then the solvent wasevaporated. The crude product was purified by chromatography to obtainthe title compound as a yellow solid (80 mg, yield 25%). LC-MS (ESI)m/z: 447 (M+1)⁺.

Example 125F8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of compound ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(80 mg, 0.18 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5mL) was stirred at room temperature for 4 h. The solvent was removed invacuum; the crude product was purified by chromatography to obtain thetitle compound as a yellow solid (22 mg, yield 30%). LC-MS (ESI) m/z:415 (M+1)⁺. 1H-NMR (400 MHz, DMSO-d6) □ δ (ppm): 2.14 (s, 6H), 3.36 (s,2H), 4.18-4.21 (d, J=8.8 Hz, 1H), 4.67-4.69 (d, J=9.2 Hz, 1H), 6.81-6.84(m, 1H), 6.99-7.01 (m, 2H), 7.08-7.19 (m, 8H).

Example 1268-(4-((3,4-Dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 126A tert-Butyl 3-methylpiperazine-1-carboxylate

To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine(6 mL) in methylene chloride (15 mL) at 0° C. was added (Boc)₂O (4.14 g,0.019 mol) dropwise. The mixture was stirred at room temperature for 1hour, and then the solvent was removed by rotary evaporation. Theresidue was dissolved in methylene chloride, washed with saturatedsodium bicarbonate and brine, dried over Na₂SO₄, and purified by columnchromatography on silica gel (DCM:MeOH:Et₃N=75:1:0.2) to give an whitesolid (1.65 g, 42%). LC-MS (ESI) m/z: 201 (M+1)⁺.

Example 126B tert-Butyl 3,4-dimethylpiperazine-1-carboxylate

tert-Butyl-3-methylpiperazine carboxylate (1.49 g, 7.45 mmol) andparaformaldehyde (1.12 g, 37.2 mmol) were dissolved in a mixture of MeOHand acetic acid (5:1) on molecular sieves. NaBCNH₃ (1.88 g, 29.8 mmol)was added to the suspension at 25° C. The slurry was subsequently heatedto 80° C. for 10 hr. Then the mixture was cooled, filtered, andconcentrated. The residue was dissolved in dichloromethane and washedwith saturated sodium bicarbonate. The organic solution was dried overNa₂SO₄, and concentrated to give a white oily (1.2 g, 90%). LC-MS (ESI)m/z: 215 (M+1)⁺.

Example 126C 1,2-Dimethylpiperazine

Trifluoroacetic acid (7 mL) was added to a solution oftert-butyl-3,4-dimethylpiperazine-1-carboxylate (1.7 g, 7.94 mmol) inmethylene chloride (15 mL) at room temperature, followed by stirring for1 hour. The residue obtained by removal of solvents by rotaryevaporation under reduced pressure to give the title compound. LC-MS(ESI) m/z: 201 (M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) □□δ (ppm): 1.21 (d, J=6.8Hz, 3H), 1.46 (s, 9H), 2.64-2.70 (m, 1H), 2.74-2.78 (m, 1H), 2.88-3.01(m, 3H), 3.78 (d, J=12.4 Hz, 1H), 4.16 (m, 1H).

Example 126D8-(4-((3,4-Dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) inmethylene chloride (10 mL) was stirred at room temperature overnight,then NaBCNH₃ (129 mg, 2.08 mmole) was added and the mixture was stirredfor another 5 hours. After removal of solvents, the residue was purifiedby column chromatography (silica gel, petroleum ether/ethyl acetate=3:1to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484(M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) □□δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84(s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H),4.65 (m, 1H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H),7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H).

Example 1278-(4-((3,5-Dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 127A 4-Benzyl 1-tert-butyl2,6-dimethylpiperazine-1,4-dicarboxylate

To a solution of 2,6-dimethylpiperazine (2.28 g, 20 mmol) in methylenechloride (15 mL) at 0° C. was added benzylchloroformate (3.0 mL)dropwise. The mixture was stirred at 0° C. for one hour then at roomtemperature for 2 hours. The mixture was cooled to 0° C.,Diisopropylethylamine (4.5 mL) was added and followed by (Boc)₂O (4.8 g,22 mmol). The mixture was stirred at room temperature overnight and thenthe solvent was removed by rotary evaporation. The residue was dissolvedin EtOAc, washed with water and brine, dried over Na₂SO₄, and purifiedby column chromatography on silica gel (EtOAc:hexane=1:9) to give anoily intermediate (4.8 g, 72%). LC-MS (ESI) m/z: 361 (M+23)⁺.

Example 127B tert-Butyl 2,6-dimethylpiperazine-1-carboxylate

A solution of 4-benzyl 1-tert-butyl2,6-dimethylpiperazine-1,4-dicarboxylate (4.8 g, 0.0144 mol) in methanol(25 mL) was added 480 mg of 10% Pd/C and stirred at room temperatureunder H₂ overnight. The resulting mixture was filtered and concentratedto give the title product (2.8 g, 97%) as colorless oil. LC-MS (ESI)m/z: 215 (M+1)⁺. ¹H-NMR (400 MHz, CDCl₃) □□ δ (ppm): 1.25 (d, J=6.8 Hz,3H), 1.46 (s, 9H), 1.64 (s, 1H), 2.78-2.87 (m, 4H), 3.99-4.05 (m, 2H).

Example 127C (2R,6R)-tert-Butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(200 mg, 520 mmol), tert-butyl 2,6-dimethylpiperazine-1-carboxylate (335mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at roomtemperature overnight, then NaBCNH₃ (129 mg, 2.08 mmol) was added andthe mixture was stirred for another 5 hours. After removal of solvents,the residue was purified by column chromatography (silica gel, petroleumether/ethyl acetate=3:1 to 1:1) to give the title compound (72 mg, 24%).LC-MS (ESI) m/z: 584 (M+1)⁺.

Example 127D8-(4-((3,5-Dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of (2R,6R)-tert-butyl4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2,6-dimethylpiperazine-1-carboxylate(72 mg, 0.12 mmol) in HCl—CH₃CN (2 mL) was stirred for 2 hours. Afterremoval of solvents, the residue was purified by prep-HPLC to afford thetitle product as a white solid (33 mg, 53%). LC-MS (ESI) m/z: 497(M+1)⁺. ¹H-NMR (400 MHz, DMSO) δ (ppm): 1.02-1.03 (d, J=6.4 Hz, 6H),1.58 (t, J=10 Hz, 1H), 2.66 (d, J=10 Hz, 1H), 2.91 (t, J=6.8 Hz, 2H),3.41 (s, 2H), 4.20 (d, J=10 Hz, 1H), 4.58 (d, J=10 Hz, 1H), 4.98 (s, 1H), 6.97 (t, J=2.4 Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=2.4 Hz,2H), 7.16 (d, J=2.4 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz,1H), 10.34 (s, 1H).

Example 1289-Phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(367 mg, 1 mmol) in dry DCM (15 mL) was added acetic acid (0.2 mL)followed by pyrrolidine (213 mg, 3 mmol). After the addition, themixture was stirred at room temperature overnight. Then sodiumborohydride (318 mg, 1.5 mmol) was added at 0° C. After the addition,the mixture was stirred at this temperature for 12 hr. DCM was removedunder reduced pressure. The residue was washed with ethylacetate/methanol (10/1) and filtered. The filtrate was concentrated togive the crude product, which was purified by prep-HPLC to give thetitle compound (62 mg, yield 14%) as white solid. LC-MS (ESI) m/z: 423(M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.82-1.85 (m, 2H), 1.97 (s,2H), 3.01-3.05 (m, 2H), 3.26 (d, 2H), 4.27 (d, 2H), 4.36 (d, 1H), 4.84(d, 1H), 7.13-7.23 (m, 6H), 7.36-7.40 (m, 5H), 7.48 (s, 1H), 7.57-7.61(t, 1H), 12.18 (s, 1H).

Example 1298-(4-(azetidin-1-ylmethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(150 mg, 0.41 mmol) in dry dichloromethane (20 mL) and MeOH (2 mL) wasadded acetic acid (120 mg) followed by azetidine (70 mg, 1.23 mmol).After the addition, the mixture was stirred at room temperatureovernight. Then sodium triacetoxyborohydride (131 mg, 0.62 mmol) wasadded at 0° C. After the addition, the mixture was stirred at thistemperature for 5 hr. DCM was removed under reduced pressure. Theresidue was washed with ethyl acetate/methanol (10/1) and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby column chromatography (silica gel, dichloromethane/methanol=100:1 to15:1) to give the title compound (84 mg, yield 51%) as yellow solid.LC-MS (ESI) m/z: 409 (M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 2.38-2.43(m, 2H), 3.98 (t, J=8 Hz, 4H), 4.20 (s, 2H), 4.27 (d, J=8 Hz, 1H), 4.77(d, J=8 Hz, 1H), 7.03-7.05 (m, 2H), 7.10-7.17 (m, 4H), 7.27-7.35 (m,4H), 7.50-7.52 (m, 1H), 7.57-7.62 (m, 1H).

Example 1309-(1-Methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.22 mmol), acetic acid (60 uL) and pyrrolidine (1.05 g, 15mmol) in acetonitrile (7 mL) was stirred at room temperature for 4 hr.To this mixture was added NaCNBH₃(36 mg, 0.67 mmol) at 0° C. After theaddition, the mixture was stirred at room temperature for 4 hr. Uponremoval of solvents under reduced pressure, the residue was washed withethyl acetate and filtered. The filtrate was concentrated to give thetitle compound as a white solid (21 mg, yield 22%). LC-MS (ESI) m/z: 427(M+1)⁺. ¹H-NMR: (400 MHz, DMSO-d₆ & D₂O) δ (ppm): 1.66 (d, J=2.8 Hz,4H), 2.37 (s, 4H), 3.38 (s, 3H), 3.50 (s, 2H), 4.62 (d, J=10 Hz, 1H),4.90 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.20 (m, 3H),7.29-7.32 (m, 3H), 7.36-7.38 (m, 1H), 7.54-7.58 (m, 1H), 12.15 (s, 1H).

Example 1319-(4-Fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 131A(E)-4-((l-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one

A solution of 1-methyl-1H-imidazole-2-carbaldehyde (680 mg, 6.18 mmol),4-aminoisobenzofuran-1(3H)-one (920.8 mg, 6.18 mmol) and anhydrousmagnesium sulfate (7.41 g, 61.8 mmol) in acetonitrile (100 ml) washeated to reflux for two days. The mixture was filtered and the solventswere removed in vacuum. The crude product was re-crystallized fromisopropanol to get the title compound (1.49 g, yield 68%). LC-MS (ESI)m/z: 242 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) □; 4.06 (s, 3H), 5.52 (s,2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.65-7.67 (m, 1H), 7.72-7.74 (m, 2H),8.66 (s, 1H).

Example 131B Ethyl3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound 4-fluorobenzaldehyde (248 mg, 2 mmol) and(E)-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one(482 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then asolution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) inethanol (5 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 0.5 hr. The mixture was quenched withwater (20 mL) and solvent was removed in vacuum. The residue wasdissolved in water and extracted with ethyl acetate three times, washedwith water and brine, and then concentrated to give the crude product,which was purified by column chromatography to obtain a yellow solid(200 mg, yield 25%). LC-MS (ESI) m/z: 394 (M+1)⁺

Example 131C9-(4-Fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(200 mg, 0.5 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5mL) was stirred at room temperature for 4 h. The resulting mixture wasfiltered and washed by water (20 mL) and methanol (5 mL) to obtain awhite solid, which was dried in vacuum at 50° C. to obtain the titlecompound (25 mg, yield 14%). LC-MS (ESI) m/z: 362 (M+1)⁺. ¹H-NMR (400MHz, DMSO-d6) □δ (ppm): 3.58 (s, 3H), 4.52-4.54 (d, J=7.2 Hz, 1H),4.94-4.97 (m, 1H), 6.69-6.70 (m, 1H), 6.96-6.97 (m, 1H), 7.04-7.08 (m,3H), 7.18-7.22 (m, 2H), 7.36-7.38 (m, 2H), 7.51-7.55 (t, J=8.0 Hz, 1H),12.2 (s, 1H).

Example 1329-(4-Fluorophenyl)-8-(quinolin-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 132A Quinoline-6-carbaldehyde

A mixture of SeO₂ (10.89 g, 99 mmol) and 6-methylquinoline (12.87 g, 90mmol) was heated to 150° C. and stirred for 16 h. Then it was cooled toroom temperature and EtOAc (400 ml) was added. After filtration, thefiltrate was concentrated to obtain the crude compound, which waspurified by chromatography (silica gel, petroleum ether/EtOAc 5:1 to2:1) to afford the title compound (2.87 g, yield 20%). LC-MS (ESI) m/z:158 (M+1)⁺.

Example 132B (E)-4-(quinolin-6-ylmethyleneamino)isobenzofuran-1(3H)-one

A solution of quinoline-6-carbaldehyde (786 mg, 5.0 mmol),4-aminoisobenzofuran-1(3H)-one (745 mg, 5.0 mmol) and anhydrousmagnesium sulfate (6.0 g, 50.0 mmol) in acetonitrile (100 ml) was heatedat reflux for two days. The solution was filtered and removed in vacuum.The crude product was re-crystallized from isopropanol to give the titlecompound (1.348 g, yield 93%) LC-MS (ESI) m/z: 289 (M+1)⁺. ¹H-NMR (400MHz, DMSO-d6) □ δ (ppm): 5.57 (s, 2H), 7.63-7.77 (m, 4H), 8.14-8.16 (d,J=8.8 Hz, 1H), 8.39-8.42 (m, 1H), 8.53-8.56 (m, 2H), 8.99-9.01 (m, 2H).

Example 132C Ethyl3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of compound 4-fluorobenzaldehyde (248 mg, 2 mmol) and(E)-4-(quinolin-6-ylmethyleneamino)isobenzofuran-1(3H)-one (576 mg, 2mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution ofsodium ethoxide in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 mL))was added dropwise. After the addition, the mixture was stirred at roomtemperature for 0.5 hr. The mixture was quenched with water (20 mL) andsolvent was removed in vacuum. The residue was dissolved in water andextracted with ethyl acetate three times. After washed with water andbrine, the solvents were removed by rotary evaporation. The crudeproduct was purified by chromatography to obtain a yellow solid. Thesolid was dried in vacuum at 50° C. to give the title compound (260 mg,yield 29%). LC-MS (ESI) m/z: 441 (M+1)⁺.

Example 132D9-(4-Fluorophenyl)-8-(quinolin-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(260 mg, 0.59 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5mL) was stirred at room temperature for 4 h. The resulting mixture wasfiltered and washed by water (20 mL) and methanol (5 mL) to obtain thetitle compound as a white solid (61 mg, yield 25%). LC-MS (ESI) m/z: 409(M+1)⁺. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.52-4.55 (d, J=9.6 Hz, 1H),4.98-5.01 (d, J=9.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H),7.41-7.43 (d, J=7.6 Hz, 1H), 7.46-7.50 (m, 1H), 7.54 (s, 1H), 7.59-7.63(t, J=7.6 Hz, 1H), 7.77-7.79 (m, 1H), 7.84 (s, 1H), 7.91-7.93 (m, 1H),8.24-8.26 (d, J=7.6 Hz, 1H), 8.85-8.86 (m, 1H), 12.20 (s, 1H).

Example 1338-(4-((Dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 133A Ethyl2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(500 mg, 1.7 mmol) and 4-methylbenzaldehyde (204 mg, 1.7 mmol) in ethylpropionate (30 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (156 mg, 6.8 mmol) in ethanol (30 mL)) wasadded dropwise. After the addition, the mixture was stirred at 10° C.for 1 hr, then at 30° C. for 3 hr. The mixture was quenched with water(30 mL) and solvent was removed in vacuum. The residue was dissolved inwater, and then extracted with ethyl acetate (30 mL×4). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated to give crude product, which was purified bychromatography (silica gel, dichloromethane/methanol=100:1 to 10:1) togive the title compound (110 mg, yield: 15%). LC-MS (ESI) m/z: 443(M+1)⁺.

Example 133B8-(4-((Dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) wasstirred at 10° C. for 2.5 h. The mixture was purified by prep-HPLC toobtain the title compound as a white solid (14 mg, yield 11%). LC-MS(ESI) m/z: 411 (M+1)⁺; ¹H-NMR (400 MHz, CD₃OD) □ δ (ppm): 2.18 (s, 3H),2.31 (s, 6H), 3.57 (s, 2H), 4.25-4.27 (d, J=8.4 Hz, 1H), 4.72-4.74 (d,J=8.4 Hz, 1H), 6.95-7.02 (m, 4H), 7.19-7.29 (m, 5H), 7.55-7.57 (m, 1H),7.62-7.64 (t, J=8 Hz, 1H).

Example 1349-(4-Chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 134A Ethyl3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(588 mg, 2 mmol) and 4-chlorobenzaldehyde (281 mg, 2 mmol) in anhydrousethyl propionate (25 mL) was cooled to 0° C. The sodium methoxide inmethanol solution (sodium (115 mg, 5 mmol) in anhydrous ethanol (10 mL))was added dropwise and the mixture was stirred at 25° C. for 3 hr. Theresulting mixture was quenched with water (5 mL), and then evaporatedunder reduced pressure. The residue was extracted with ethyl acetate(100 mL×3) and the combined organic layers were dried over anhydroussodium sulfate and concentrated to give crude product, which waspurified by column chromatography (silica gel, dichloromethane todichloromethane/methanol=30:1) to give the title compound (260 mg, yield28%) as a yellow solid. LC-MS (ESI) m/z: 463 (M+1)⁺.

Example 134B9-(4-Chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(260 mg, 0.56 mmol) and hydrazine monohydrate (3 mL) in methanol (20 mL)was stirred at 30° C. for 4 hr. The mixture was concentrated to givecrude product, which was purified by prep-HPLC to give the titlecompound (34 mg, yield 14%) as a white solid of formic acid salt. LC-MS(ESI) m/z: 431 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): □2.66 (s, 6H),4.20-4.21 (d, J=4.8 Hz, 2H), 4.39-4.42 (d, J=8.8 Hz, 1H), 4.82-4.84 (d,J=8.8 Hz, 1H), 7.15-7.20 (m, 4H), 7.25-7.27 (d, 2H), 7.35-7.42 (m, 5H),7.46 (s, 1H), 7.58-7.62 (t, J=8.0 Hz, 1H), 9.74 (br s, 1H), 12.18 (s,1H).

Example 1358-(4-((Dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 135A Ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of 4-methoxybenzaldehyde (231 mg, 1.7 mmol) and(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(500 mg, 1.7 mmol) in ethyl propionate (30 mL) was added sodiummethanolate (120 mg, 5.2 mmol) and the mixture was stirred at 25° C. for4 h. Then the resulting mixture was added water (10 mL) and evaporatedunder reduced pressure, extracted with EtOAc (4×100 ml), andconcentrated to dryness. A crude product was obtained (250 mg) and wasused for next step reaction without further purification. LC-MS (ESI)m/z: 459 (M+1)⁺.

Example 135B8-(4-((Dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(70 mg, 0.15 mmol) and hydrazine monohydrate (1 mL) in methanol (5 mL)was stirred at room temperature for 5 hr. The resulting mixture wasevaporated under reduced pressure to a volume of 1 mL and then filtered.The filtrate was concentrated to give the title compound as a whitesolid (26.5 mg). LC-MS (ESI) m/z: 427 (M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 2.79 (s, 6H), 3.71 (s, 3H), 4.24 (s, 2H), 4.26 (d, 1H), 4.77 (d,1H), 6.74 (d, 2H), 6.99 (d, 2H), 7.18-7.21 (m, 1H), 7.35-7.43 (m, 4H),7.55-7.57 (m, 1H), 7.65 (t, 3H).

Example 1368-(4-((Diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(80 mg, 0.22 mmol), diethylamine (47 mg, 0.65 mmol) and acetic acid (39mg, 0.65 mmol) in dichloromethane (50 mL) was stirred at roomtemperature for 60 min. Upon cooling the mixture to 0° C., sodiumtriacetoxyborohydride (69.3 mg, 0.33 mmol) was added. After theaddition, the mixture was stirred at room temperature overnight.Dichloromethane was removed under reduced pressure. The crude productwas purified by chromatography (silica gel,dichloromethane/Methanol=50:1) to give the title compound (34 mg, yield36%). LC-MS (ESI) m/z: 425 (M+H)⁺. ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 1.10(t, 6H), 2.64 (q, 4H), 3.70 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.75 (d,J=8.0 Hz, 1H), 7.06-7.09 (m, 2H), 7.13-7.20 (m, 4H), 7.22-7.29 (m, 4H),7.54-7.56 (dd, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H).

Example 1378-(4-((Diethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde(260 mg, 0.68 mmol) in dryness DCM (15 mL) was added acetic acid (0.2mL) followed by diethylamine (148 mg, 2.03 mmol). After the addition,the mixture was stirred at room temperature overnight. Then sodiumborohydride (212 mg, 1.01 mmol) was added to the mixture at 0° C. Themixture was stirred at this temperature for 12 hr. DCM was removed underreduced pressure. The residue was washed with ethyl acetate/methanol(10/1) and filtered. The filtrate was concentrated to give the crudeproduct, which was purified by flash chromatography to give the titlecompound as white solid (27.3 mg, yield 9%). LC-MS (ESI) m/z: 442(M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ (ppm): 3.12-3.17 (m, 4H), 4.27 (s,2H), 4.34 (d, 1H), 4.78 (d, 1H), 6.91 (t, 2H), 7.09-7.12 (m, 1H),7.38-7.45 (m, 4H), 7.56-7.58 (m, 1H), 7.64 (t, 1H).

Example 1389-(4-Chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 138A(E)-4-(4-((diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one

To a stirred mixture of 4-((diethylamino)methyl)benzaldehyde (3.7 g,19.4 mmol) and anhydrous magnesium sulfate (11.6 g, 96.8 mmol) inanhydrous acetonitrile (100 mL) was added 4-aminoisobenzofuran-1(3H)-one(2.89 g, 19.4 mmol) at 0° C. After the addition the mixture was stirredrefluxed for 3 days. The mixture was filtered and the cake was washedwith ethyl acetate (50 mL×3). The filtrate was concentrated to givecrude product, which was re-crystallized from isopropanol to give thetitle compound (2.1 g, yield: 32%). LC-MS (ESI) m/z: 323 (M+1)⁺.

Example 138B Ethyl3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(500 mg, 1.55 mmol) and 4-chlorobenzaldehyde (218 mg, 1.55 mmol) inethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (107 mg, 4.66 mmol) in ethanol (5 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product, which was purified by chromatography(silica gel, petroleum ether/ethyl acetate=1:1) to give the crude of thetitle compound (268 mg, yield 35%). LC-MS (ESI) m/z: 491 (M+1)⁺.

Example 138C9-(4-Chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(268 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol (2 mL) wasstirred at 23° C. for overnight. Methanol was removed under reducedpressure. The crude was purified by prep-HPLC to give the title compound(93 mg, yield 37%). LC-MS (ESI) m/z: 459 (M+1)⁺. ¹H-NMR (400 MHz,DMSO-d6) δ (ppm): 0.93 (t, 6H), 2.38 (q, 4H), 3.44 (s, 2H), 4.35 (d,1H), 4.73 (d, 1H), 7.13-7.19 (m, 5H), 7.22-7.25 (m, 4H), 7.38 (d, 2H),7.41 (s, 1H), 7.56-7.59 (m, 1H).

Example 1395-Fluoro-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 139A(E)-6-Fluoro-4-((l-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one

A solution of 1-methyl-1H-imidazole-2-carbaldehyde (659 mg, 6.0 mmol),4-amino-6-fluoroisobenzofuran-1(3H)-one (1.0 g, 6.0 mmol), and anhydrousmagnesium sulfate (7.2 g, 60.0 mmol) in acetonitrile (100 mL) was heatedto reflux for 2 days. The solution was filtered and the solvents wereremoved in vacuum. The crude product was re-crystallized fromisopropanol to afford the title compound (1.068 g, yield 68%) LC-MS(ESI) m/z: 260 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.04 (s, 3H),5.49 (s, 2H), 7.24 (s, 1H), 7.54-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.70(s, 1H).

Example 139B Ethyl7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of benzaldehyde (212 mg, 2 mmol) and(E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one(518 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then asolution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) inethanol (5 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 0.5 hr. The mixture was quenched withwater (20 mL) and solvent was removed in vacuum. The residue wasdissolved in water and extracted with ethyl acetate three times. Thecombined organic layers were washed by water and brine, and thenevaporated to dryness, the crude product was purified by chromatographyto obtain a yellow solid. The solid was dried in vacuum at 50° C. togive the title compound (250 mg, yield 32%). LC-MS (ESI) m/z: 394(M+1)⁺.

Example 139C5-Fluoro-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(250 mg, 0.636 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5mL) was stirred at room temperature for 4 h. The resulting mixture waxfiltered and washed water (20 mL) and methanol (5 mL) to obtain a whitesolid, which after dried in vacuum at 50° C. afforded the title compound(34.6 mg, yield 15%). LC-MS (ESI) m/z: 362 (M+1)⁺; 1H-NMR (400 MHz,DMSO-d6) □ δ (ppm): 3.56 (s, 3H), 4.48-4.49 (d, J=6.0 Hz, 1H), 5.01-5.03(m, 1H), 6.70-6.71 (m, 1H), 6.81-6.84 (m, 1H), 6.98-7.02 (m, 2H),7.14-7.26 (m, 5H), 7.66-7.67 (m, 1H), 12.33 (s, 1H).

Example 1405-Fluoro-9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 140A Ethyl7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of 4-fluorobenzaldehyde (248 mg, 2 mmol) and(E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one(518 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then asolution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) inethanol (5 mL)) was added dropwise. After the addition, the mixture wasstirred at room temperature for 0.5 hr. The mixture was quenched withwater (20 mL) and solvents were removed in vacuum. The residues weredissolved in water and extracted with ethyl acetate three times. Thecombined organic layers were washed with water and brine. After theremoval of solvents, the crude product was purified by flash columnchromatography to obtain a yellow solid, which was dried in vacuum at50° C. to give the title compound (200 mg, yield: 24%). LC-MS (ESI) m/z:412 (M+1)⁺.

Example 140B5-Fluoro-9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(200 mg, 0.486 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5mL) was stirred at room temperature for 4 h. The resulting mixture wasfiltered and washed by water (20 mL) and methanol (5 mL) to obtain awhite solid, which was then dried in vacuum at 50° C. to obtain thetitle compound (25.4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)⁺; 1H-NMR(400 MHz, DMSO-d6) □ δ (ppm): 3.56 (s, 3H), 4.52-4.53 (d, J=6.8 Hz, 1H),5.02-5.04 (m, 1H), 6.73 (s, 1H), 6.82-6.85 (m, 1H), 6.99-7.09 (m, 4H),7.18-7.22 (m, 2H), 7.69 (s, 1H), 12.34 (s, 1H).

Example 1418-(4-((Dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 141A Ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(588 mg, 2 mmol) and 4-ethylbenzaldehyde (268 mg, 2 mmol) in ethylpropionate (15 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product, which was purified by chromatography(silica gel, petroleum ether/ethyl acetate=1:1) to give the crude titlecompound (290 mg, yield 32%). LC-MS (ESI) m/z: 457 (M+1)⁺.

Example 141B8-(4-((Dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(290 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) wasstirred at 30° C. for overnight. Methanol was removed under reducedpressure. The crude product was purified by chromatography (silica gel,Petroleum ether/ethyl acetate=1:1) to give the title compound (112 mg,yield 42%). LC-MS (ESI) m/z: 425 (M+1)⁺. ¹H-NMR (400 MHz, CD₃OD) δ(ppm): 1.12 (t, 3H), 2.10 (s, 6H), 2.52 (q, 2H), 3.34 (s, 2H), 4.31 (d,J=8.0 Hz, 1H), 4.76 (d, J=8.0 Hz, 1H), 7.04 (m, 4H), 7.15-7.20 (m, 3H),7.25-7.27 (m, 2H), 7.38-7.41 (m, 3H), 7.59-7.61 (m, 1H).

Example 1428-(4-((Dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 142A Ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(588 mg, 2 mmol) and 4-isopropylbenzaldehyde (296 mg, 2 mmol) in ethylpropionate (15 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product, which was then purified by columnchromatography (silica gel, petroleum ether/ethyl acetate=1:1) to givethe title compound (210 mg, yield 22%). LC-MS (ESI) m/z: 471 (M+1)⁺.

Example 142B8-(4-((Dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(210 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) wasstirred at 23° C. for overnight. Methanol was removed under reducedpressure. The crude was purified by flash chromatography to give thetitle compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)⁺. ¹H-NMR(400 MHz, CD₃OD) δ (ppm): 1.18 (d, 3H), 1.19 (d, 3H), 2.26 (s, 6H),2.79-2.83 (m, 1H), 3.51 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0Hz, 1H), 6.98-7.00 (m, 2H), 7.05-7.07 (m, 2H), 7.18-7.22 (m, 3H),7.25-7.27 (m, 2H), 7.54-7.56 (m, 1H), 7.56-7.59 (m, 1H).

Example 1438-(4-((Dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 143A Ethyl2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(541 mg, 1.84 mmol) and 4-(trifluoromethyl)benzaldehyde (320 mg, 1.84mmol) in anhydrous ethyl propionate (25 mL) was cooled to 0° C. Thensodium ethoxide in methanol solution (sodium (127 mg, 5.51 mmol) inanhydrous ethanol (10 mL)) was added dropwise and the mixture wasstirred at 25° C. for 4 hr. The resulting mixture was quenched withwater (5 mL), and then evaporated the solvents off under reducedpressure. The residue was extracted with ethyl acetate (100 mL×3) andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated to give crude product, which was purified by columnchromatography (silica gel, dichloromethane todichloromethane/methanol=30:1) to give the title compound (150 mg, yield16%) as a yellow solid. LC-MS (ESI) m/z: 497 (M+1)⁺.

Example 143B8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg, 0.30 mmol) and hydrazine monohydrate (0.5 mL) in methanol (10mL) was stirred at 30° C. overnight. The mixture was concentrated underreduced pressure to give crude product, which was purified by flashchromatography to give the title compound (60 mg, yield 34.5%) as awhite solid. LC-MS (ESI) m/z: 465 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm) □: 2.64 (s, 3H), 2.65 (s, 3H), 4.19-4.20 (d, J=4.0 Hz, 2H),4.53-4.55 (d, J=9.2 Hz, 1H), 4.88-4.90 (d, J=9.2 Hz, 1H), 7.20-7.22 (d,J=7.6 Hz, 1H), 7.35-7.46 (m, 7H), 7.50 (s, 1H), 7.56-7.63 (m, 3H),9.69-9.71 (br s, 1H), 12.20 (s, 1H).

Example 1448-(4-((Diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 144A Ethyl2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-((diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one(644 mg, 2 mmol) and 4-methylbenzaldehyde (240 mg, 2 mmol) in ethylpropionate (15 mL) was cooled to 0° C. Then a solution of sodiumethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) wasadded dropwise. After the addition, the mixture was stirred at roomtemperature for 3 hr. The mixture was quenched with water (10 mL) andsolvent was removed in vacuum. The residue was dissolved in water, andthen extracted with ethyl acetate (100 mL×4). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated to give crude product, which was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate=1:1) to givethe title compound (320 mg, yield 34%). LC-MS (ESI) m/z: 471 (M+1)⁺.

Example 144B8-(4-((Diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(320 mg) in hydrazine monohydrate (2 mL, 85%) and methanol (10 mL) wasstirred at 30° C. for overnight. Methanol was removed under reducedpressure. The crude product was purified by chromatography (silica gel,petroleum ether/ethyl acetate=1:1) to give the title compound (85 mg,yield 29%). LC-MS (ESI) m/z: 439 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm): 0.93 (t, 6H), 2.20 (s, 3H), 2.39 (q, 4H), 3.42 (d, 2H), 4.27 (d,J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 4H), 7.15-7.17 (m,3H), 7.22-7.24 (m, 2H), 7.35-7.38 (m, 2H), 7.54-7.56 (m, 1H), 12.12 (s,1H).

Example 1459-(4-Fluorophenyl)-8-(4-(1-methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 145A tert-Butyl 2-oxopyrrolidine-1-carboxylate

To a solution of 2-pyrrolidinone (10.82 g, 127 mmol) in acetonitrile(400 mL) was added DMAP (1.53 g, 12.6 mmol), followed by a solution ofdi-tert-butyldicarbonate (33.6 g, 77.1 mmol) in acetonitrile (20 mL).The reaction mixture was stirred at room temperature for 1 h. Theresulting mixture was concentrated in vacuo and the resulting oil wastaken up in diethyl ether. The mixture was washed consecutively with 1 NHCl and brine. The organic phase was dried over sodium sulfate, andconcentrated in vacuo to afford the title compound as a yellow oil (15g, 64%) which was used directly in the next step.

Example 145B tert-Butyl 4-(4-bromophenyl)-4-oxobutylcarbamate

A thoroughly dried three-necked round-bottom flask was equipped withreflux condenser, addition funnel and argon inlet. Then magnesium powder(7.5 g, 311 mmol, activated by iodine) and dry THF (300 mL) were placedinto this apparatus. A solution of 1, 4-dibromobenzene (73.5 g, 311mmol) in dry THF (200 mL) was slowly added at such a rate that themixture maintained at reflux. When the addition was completed themixture was refluxed for additional 2 hrs. After cooling to roomtemperature, the solution was added into a solution of tert-butyl2-oxopyrrolidine-1-carboxylate (48 g, 260 mmol) in THF (320 mL) at −78°C. and the mixture was stirred at −78° C. for 2 hrs. The solution waswarmed to ambient temperature and stirred for another 10 hrs beforequenching with water. Hydrochloric acid (1 N, 100 mL) was added and themixture was stirred at ambient temperature for 10 minutes. The mixturewas concentrated and the residue was partitioned between ethyl acetateand brine. The organic phase was dried over magnesium sulfate andconcentrated in vacuo to afforded the crude product, which was purifiedby column chromatography (EtOAc:DCM:hexane=1:1:15) to give the titlecompound as a white solid (53 g, yield 60%). LC-MS (ESI) m/z: 342(M+1)⁺.

Example 145C 5-(4-Bromophenyl)-3,4-dihydro-2H-pyrrole

tert-Butyl 4-(4-bromophenyl)-4-oxobutylcarbamate (3.42 g, 10 mmol) wasstirred in TFA (10 mL) for 6 hrs. Then 50% NaOH solution was added tothe mixture to make pH=13-14, the white precipitate was filtrated,washed with water and dried to give the title compound as a white solid(1.8 g, yield 80%). LC-MS (ESI) m/z: 224 (M+1)⁺.

Example 145D 2-(4-Bromophenyl)pyrrolidine

NaBH₄ (1.52 g, 40 mmol) was added to a solution of5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole (4.48 g, 20 mmol) in H₂O/MeOH(30 mL, v/v 1:4) at −41° C. After stirred for 4 hrs, the solution wasallowed to warm to room temperature. Once the reaction was deemedcomplete by TLC, the unreacted NaBH₄ was quenched by the addition of 2 NHCl. The solution was then diluted with water and ether, and separatedtwo layers. The aqueous layer was washed with an additional portion ofether, basified with 4 M NaOH (pH 12-13) and washed with ethyl acetate.The combined organic extracts were washed with brine, and then driedover Na₂SO₄. Evaporation of the solvent afforded the title crude productas a yellow oil (3.8 g, yield 84%), which was used directly in the nextstep. LC-MS (ESI) m/z: 226 (M+1)⁺.

Example 145E 2-(4-Bromophenyl)-1-methylpyrrolidine

A mixture of 2-(4-bromophenyl)pyrrolidine (0.5 g, 2.2 mmol), formic acid(0.11 mL, 2.42 mmol), formaldehyde (0.2 mL, 2.42 mmol, 37% in water),water (4 mL) in a sealed tube was heated to 150° C. under microwave for5 minutes. After cooling to room temperature the reaction mixture wasextracted with EtOAc (3×15 mL), the combined organic phase was washedconsecutively with saturated NaHCO₃(5 mL) and brine (5 mL), dried overNa₂SO₄ and concentrated in vacuo to give the crude product (0.48 g,91%), which was used directly in the next step. LC-MS (ESI) m/z: 240(M+1)⁺.

Example 145F 4-(1-Methylpyrrolidin-2-yl)benzaldehyde

To a solution of 2-(4-bromophenyl)-1-methylpyrrolidine (0.45 g, 2 mmol)in dry THF (10 mL) was added dropwise n-BuLi (0.88 mL, 2.2 mmol, 2.5mol/L in hexane) at −78° C., after the addition was completed themixture was stirred for 1 h, then dry DMF (0.18 mL, 2.4 mmol) was addedto the reaction system and stirring was continued for another 1 hr. Thenthe reaction mixture was partitioned between EtOAc and 1 N HCl, theaqueous solution was extracted with EtOAc (3×15 mL). The combinedorganic phase was washed with brine, dried over Na₂SO₄, and concentratedin vacuo to give crude product (0.28 g, yield 74%) as a yellow oil. Theproduct was used directly in the next step without further purification.LC-MS (ESI) m/z: 189 (M+1)⁺.

Example 145G(E)-4-(4-(1-methylpyrrolidin-2-yl)benzylideneamino)isobenzofuran-1(3H)-one

A mixture of 4-(1-methylpyrrolidin-2-yl)benzaldehyde (1.89 g, 10 mmol),4-aminoisobenzofuran-1(3H)-one (1.49 g, 10 mmol) and MgSO₄(12 g, 100mmol) in CH₃CN (60 mL) was refluxed at 120° C. for 4 days. After a hotfiltration, CH₃CN was partially removed under reduced pressure and awhite precipitate was appeared, the title compound was obtained by adirect filtration (1.3 g, yield 41%) as a white solid. LC-MS (ESI) m/z:440 (M+1)⁺.

Example 145H Ethyl3-(4-fluorophenyl)-2-(4-(1-methylpyrrolidin-2-yl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A mixture of(E)-4-(4-(1-methylpyrrolidin-2-yl)benzylideneamino)isobenzofuran-1(3H)-one(0.32 g, 1 mmol), 4-flourobenzenaldehyde (0.248 g, 2 mmol) was dissolvedin dry ethyl propionate (5 mL), EtONa (0.136 g, 2 mmol) in EtOH (5 mL)was added to this solution and the mixture was stirred at roomtemperature until the starting material was disappeared as monitored byTLC. The reaction was quenched with 0.5 mL of water, the resultingmixture was concentrated in vacuo, and the residue was purified bycolumn chromatography (MeOH:DCM=1:20) to give the title compound (200mg, yield 42%) as a pale yellow solid. LC-MS (ESI) m/z: 472 (M+1)⁺.

Example 14519-(4-Fluorophenyl)-8-(4-(1-methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a stirred solution of ethyl3-(4-fluorophenyl)-2-(4-(1-methylpyrrolidin-2-yl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(200 mg, 0.42 mmol) in MeOH (20 ml) was added N₂H₄.H₂O (2 mL), themixture was stirred for 4 hrs, and then concentrated in vacuo and theresidue was purified by chromatography (MeOH:DCM=1:20) to give the titlecompound as a white solid (45 mg, yield 24%). LC-MS (ESI) m/z: 440(M+1)⁺; ¹H-NMR (400 MHz, CDCl₃) □ δ (ppm): 1.67-1.97 (m, 3H), 2.11 (s,3H), 2.25 (m, 1H), 2.17-2.30 (m, 1H), 2.97-2.99 (m, 1H), 3.21-3.25 (m,1H), 4.19-4.22 (d, J=10.4 Hz, 1H), 4.57-4.59 (d, J=10.4 Hz, 1H), 4.90(s, 1H), 6.86-6.91 (m, 2H), 6.95-6.97 (m, 2H), 7.03-7.05 (d, J=7.6 Hz,1H), 7.10-7.12 (d, J=8 Hz, 2H), 7.20-7.22 (d, J=8 Hz, 2H), 7.57-7.61 (t,J=7.6 Hz, 1H), 7.74-7.76 (d, J=7.6 Hz, 1H), 9.94 (s, 1H).

Example 1469-(4-Fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 146A Benzyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate

A solution of 2-(4-bromophenyl)pyrrolidine (2.26 g, 10 mmol) in dioxane(18 mL) and water (12 mL) was added potassium carbonate (5.52 g, 40 mol)and benzyl chloroformate (1.88 g, 11 mmol) at ambient temperature andstirred overnight. Then the mixture was partitioned between ethylacetate and brine. The organic phase was concentrated in vacuo and theresidue was purified by column chromatography (silica gel,EtOAc:hexane=1:10) to give the title compound (2.95 g, 82%) as acolorless oil. LC-MS (ESI) m/z: 360 (M+1)⁺.

Example 146B Benzyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate

To a 50 mL round-bottomed flask were placed Pd (PPh₃)₂Cl₂ (70 mg, 0.1mmol), and sodium formate (510 mg, 7.5 mmol) and purged with carbonmonoxide. DMF (7 mL) and benzyl2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.8 g, 5 mmol) were addedvia syringes. The mixture was vigorously stirred at 100° C. under carbonmonoxide atmosphere for 8 hrs. Then the reaction mixture was cooled toroom temperature and partitioned between ether (100 mL) and water (15mL). The organic phase was washed with water (3×15 mL), dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, EtOAc:hexane=1:10) to give the titlecompound (0.31 g, yield 20%) as a colorless oil. LC-MS (ESI) m/z: 309(M+1)⁺; ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.73-1.88 (m, 3H), 2.31-2.41(m, 1H), 3.57-3.67 (m, 2H), 4.84-5.06 (m, 3H), 6.84-6.86 (m, 1H),7.12-7.34 (m, 4H), 7.41-7.43 (d, J=8.0 Hz, 2H), 7.85-7.87 (d, J=8.0 Hz,2H), 9.98-9.99 (d, J=6.0 Hz, 1H).

Example 146C (E)-benzyl2-(4-((l-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)phenyl)pyrrolidine-1-carboxylate

A mixture of benzyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate (0.62 g,2 mmol), 4-aminoisobenzofuran-1(3H)-one (0.298 g, 2 mmol), MgSO₄ (2.4 g,20 mmol) in CH₃CN (20 mL) was refluxed at 120° C. for 4 days. After ahot filtration, the filtrate was concentrated in vacuo and the residuewas purified by column chromatography (EtOAc:DCM:hexane=1:1:6) to givethe title compound (0.35 g, yield 30%) as a white solid. LC-MS (ESI)m/z: 440 (M+1)⁺.

Example 146D Ethyl2-(4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A solution of (E)-benzyl2-(4-((1-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)phenyl)pyrrolidine-1-carboxylate(0.5 g, 1.14 mmol) and 4-flourobenzaldehyde (0.284 g, 2.28 mmol) in dryethyl propionate (5 mL) was added EtONa (0.155 g, 2.28 mmol) in EtOH (6mL), and the mixture was stirred at room temperature until the startingmaterial was disappeared as monitored by TLC. Then the reaction mixturewas quenched with 0.5 mL of water, the resulting mixture wasconcentrated in vacuo, and the residue was purified by columnchromatography to give the title compound (130 mg, yield 20%) as ayellow solid. LC-MS (ESI) m/z: 592 (M+1)⁺.

Example 146E

Benzyl2-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)pyrrolidine-1-carboxylate

To a stirred solution of ethyl2-(4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(130 mg, 0.22 mmol) in MeOH (20 mL) was added N₂H₄.H₂O (2 mL), thereaction was continued for 4 hrs, then mixture was concentrated in vacuoand the residue was purified by chromatography (EtOAc:hexane=1:2) togive the title compound (100 mg, yield 81%) as a white solid. LC-MS(ESI) m/z: 560 (M+1)⁺¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.77-1.90 (m, 3H),2.25 (m, 1H), 3.65-3.68 (m, 2H), 4.10-4.23 (m, 2H), 4.59-4.61 (d, J=10.0Hz, 1H), 4.90-5.14 (m, 2H), 6.82-7.09 (m, 10H), 7.27-7.32 (m, 2H), 7.37(s, 2H), 7.60-7.64 (m, 1H), 7.77-7.79 (m, 1H), 9.61 (s, 1H).

Example 146F9-(4-Fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Benzyl2-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)pyrrolidine-1-carboxylate(60 mg, 0.107 mmol) was dissolved in distilled methanol (15 mL), and thereaction mixture was stirred at room temperature under an atmosphere ofhydrogen in the presence of a catalytic amount of palladium on carbon(11 mg, 0.01 mmol) for 2 hrs. After the reaction was completed, thecatalyst was removed by filtration through a pad of Celite, and thesolvent was removed under reduced pressure. The residue was purified bypreparative TLC (MeOH:DCM=1:10) to give the title compound (5 mg, yield11%) as a white foam. LC-MS (ESI) m/z: 426 (M+1)⁺¹H-NMR (400 MHz, CD₃OD)□ δ (ppm): 1.78-1.88 (m, 1H), 1.95-2.08 (m, 2H), 2.24-2.32 (m, 1H),3.05-3.12 (m, 1H), 3.21-3.27 (m, 1H), 4.17-4.21 (m, 1H), 4.34-4.36 (d,J=8.0 Hz, 1H), 4.75-4.77 (d, J=8.0 Hz, 1H), 6.91-6.95 (m, 2H), 7.09-7.15(m, 2H), 7.17-7.25 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.34 (m, 4H),7.55-7.57 (m, 1H), 7.63-7.67 (m, 1H).

Example 1478-(4-Fluorophenyl)-9-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 147A Ethyl2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of ethyl2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(150 mg, 0.38 mmol) and cesium carbonate (268 mg, 0.76 mmol) in DMF (10mL) was added iodomethane (0.2 mL, 2.28 mmol) at 0° C. under N2. Thereaction mixture was stirred at 0° C. for 4 h and then at roomtemperature overnight. The resulting solution was added 50 mL of water,and then extracted with ethyl acetate (100 mL×3). The extracts wereconcentrated to give the crude product as a yellow solid (145 mg, yield90%), which was used in the next step without further purification.LC-MS (ESI) m/z: 408 (M+1)⁺.

Example 147B8-(4-Fluorophenyl)-9-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

Ethyl2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(70 mg, 0.18 mmol) was added to hydrazine monohydrate (5 mL) and themixture was stirred at 67° C. for 10 hr. The resulting mixture wasconcentrated and purified by prep-HPLC to obtain the title compound as awhite solid (9 mg, yield 14%). LC-MS (ESI) m/z: 376 (M+1)⁺. ¹H-NMR (400MHz, DMSO-d₆) □□ δ (ppm): 1.79 (s, 3H), 2.57 (s, 3H), 4.50 (s, 1H),6.68-6.69 (d, J=0.9 Hz, 1H), 6.78-6.82 (m, 2H), 6.84-6.85 (d, J=0.9 Hz,1H), 7.05-7.09 (m, 2H), 7.16-7.18 (dd, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 7.34(s, 1H), 7.43-7.45 (dd, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 7.57-7.61 (t, J=7.6Hz, 1H), 12.30 (s, 1H).

Example 1489-(4-Fluorophenyl)-8-(1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 148A 1-Benzyl-1H-imidazole-2-carbaldehyde

To a solution of 1H-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) andpotassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 mL) at 0° C.was added dropwise (bromomethyl)benzene (493 mg, 2.88 mmol). The mixturewas stirred at 40° C. for 4 hr. Then the mixture was filtrated,evaporated to remove the acetonitrile from the filtrate, added EtOAc toextract the residues, and washed the extract with brine and water. Theorganic layer was dried with anhydrous Na₂SO₄, concentrated, andchromatographed on a silica gel column (EtOAc:hexane=1:9) to obtain thetitle compound (430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+1)⁺.

Example 148B(E)-4-((1-Benzyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one

The mixture of 1-benzyl-1H-imidazole-2-carbaldehyde (430 mg, 1.48 mmol),4-aminoisobenzofuran-1(3H)-one (221 mg, 1.48 mmol) and magnesium sulfate(4.3 g) in acetonitrile was heated to reflux for 48 hr. Then the mixturewas filtrated off and evaporated to remove the solvent. The crude wasre-crystallized from isopropanol to obtain the title compound (470 mg,65%). LC-MS (ESI) m/z: 318 (M+1)⁺.

Example 148C Ethyl2-(1-benzyl-1H-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

A solution of(E)-4-((l-benzyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one(470 mg, 1.48 mmol) in ethyl propanate (5 mL) was added EtONa/EtOH (136mg of sodium in 5 mL of ethanol) and stirred at room temperature underN2 for 30 min. Then the mixture was partitioned between water and ethylacetate. The organic layer was separated, washed with water and brine,dried with anhydrous Na₂SO₄, and chromatographed on a silica gel column(EtOAc:hexane=1:9 to 1:1) to obtain the title compound (280 mg, yield40%). LC-MS (ESI) m/z: 470 (M+1)⁺.

Example 148D8-(1-Benzyl-1H-imidazol-2-yl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl2-(1-benzyl-1H-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(280 mg, 0.59 mmol) and hydrazine monohydrate (2 mL, 85%) in methanol (4mL) was stirred at 40° C. for 2 hr, and then evaporated to half of theoriginal volume. The mixture was filtrated and washed the solid withethyl acetate to obtain the title compound (200 mg, yield 96%). LC-MS(ESI) m/z: 437 (M+1)⁺.

Example 148E9-(4-Fluorophenyl)-8-(1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of8-(1-benzyl-1H-imidazol-2-yl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(200 mg, 0.46 mmol) and palladium hydroxide (200 mg) in methanol (4 mL)was purged with hydrogen and stirred at 60° C. for 18 hr. Then themixture was filtered, evaporated to remove the solvent, and washed thesolid with ethyl acetate to obtain the title compound (150 mg, yield94%). LC-MS (ESI) m/z: 348 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d6) □□ δ (ppm):4.93 (d, J=8.4 Hz, 1H), 5.21 (d, J=8.4 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H),7.21-7.30 (m, 3H), 7.37 (s, 1H), 7.45-7.49 (m, 3H), 4.58 (d, J=10 Hz,1H), 7.62-7.67 (m, 1H), 7.87 (s, 1H).

Example 1495-Fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 149A Ethyl7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (1.25 g, 4.9mmol), anhydrous Na₂SO₃(1.24 g, 9.82 mmol), anhydrous Na₂SO₄ (2 g, 14.7mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (900 mg, 8.1 mmol)in ethyl propionate (50 mL) was added EtONa [(sodium 316 mg, 13.8 mmol)in 25 mL ethanol] at 40° C., then the mixture was stirred at 40° C. for3 hr. The resulting mixture was evaporated under reduced pressure,extracted with ethyl acetate (100 mL×4) and concentrated to dryness. Thecrude product was purified by column chromatography (silica gel,dichloromethane:methanol=200:1 to 50:1) to obtain the title compound asa green solid (190 mg, yield 10%). LC-MS (ESI) m/z: 395 (M+1)⁺.

Example 149B5-Fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate(186 mg, 0.47 mmol) in methanol (1 mL) was added hydrazine monohydrate(0.5 mL), and the mixture was stirred at 25° C. for 15 hr. Then themixture was filtered to obtain a white solid (40 mg, yield 24%). LC-MS(ESI) m/z: 363 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□ δ (ppm): 3.63 (s,3H), 4.94-5.03 (m, 2H), 6.91-6.94 (dd, J₁=11.6 Hz, J₂=2.4 Hz, 1H),7.05-7.08 (dd, J₁=9.6 Hz, J₂=2.4 Hz, 1H), 7.29-7.35 (m, 3H), 7.42-7.48(m, 2H), 7.74 (s, 1H), 7.79 (s, 1H), 12.34 (s, 1H).

Example 1509-(4-Fluorophenyl)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 150A Ethyl3-(4-fluorophenyl)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a mixture of(E)-4-((l-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one(590 mg, 2.4 mmol) and 4-fluorobenzaldehyde (300 mg, 2.4 mmol) in ethylpropionate (20 mL) was added a solution of sodium ethoxide in ethanol[sodium (220 mg, 9.6 mmol) in ethanol (10 mL)]. After the addition, themixture was stirred at room temperature overnight. The mixture wasquenched with water (10 mL) and solvent was removed in vacuum. Theresidue was dissolved in water, and then extracted with ethyl acetate(100 mL×4). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated to give a crude product,which was purified by flash chromatography to give the title compound(100 mg, yield 10%). LC-MS (ESI) m/z: 410 (M+1)⁺.

Example 150B9-(4-Fluorophenyl)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A mixture of ethyl3-(4-fluorophenyl)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(60 mg) in 85% hydrazine monohydrate (0.2 mL) and methanol (2 mL) wasstirred at room temperature for 1 hr. Then the solvent was removed underreduced pressure. The residue was purified by prep-TLC(methanol:dichloromethane=1:20) to give the title compound (50 mg, yield80%). LC-MS (ESI) m/z: 378 (M+1)⁺; ¹H-NMR (400 MHz, DMSO-d6) □; 3.44 (s,3H), 5.24 (s, 1H), 6.84 (s, 1H), 6.98-7.06 (m, 4H), 7.11-7.13 (d, J=8.0Hz, 1H), 7.38-7.42 (m, 3H), 7.46 (s, 1H), 7.56-7.60 (t, J=8.0 Hz, 1H).

Example 1518-(4-Fluorophenyl)-8-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 151A(E)-4-(1-(4-Fluorophenyl)ethylideneamino)isobenzofuran-1(3H)-one

To a solution of 4-aminoisobenzofuran-1(3H)-one (1 g, 6.7 mmol) and1-(4-fluorophenyl)ethanone (1.4 g, 10.1 mmol) in toluene (35 mL) wasadded anhydrous magnesium sulfate (8.8 g, 73.7 mmol) and acetic acid(0.2 mL) at room temperature under N₂. The reaction mixture was thenstirred at 120° C. for 36 hr. The reaction mixture was cooled to 90° C.and filtered. After filter cake was washed with acetonitrile, thefiltrates were combined and evaporated to dryness to obtain yellowsolid, which was washed by petroleum ether to obtain the title compoundas a white solid (1.58 g, yield 88%). LC-MS (ESI) m/z: 270 (M+1)⁺¹H-NMR(400 MHz, CDCl₃) □□ δ (ppm): 2.30 (s, 3H), 5.16 (s, 2H), 7.00-7.02 (d,J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.51-7.56 (t, J=7.6 Hz, 1H), 7.66-7.69(d, J=7.6 Hz, 1H), 7.99-8.03 (m, 2H).

Example 151B Ethyl2-(4-fluorophenyl)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of 1-methyl-1H-imidazole-2-carbaldehyde (580 mg, 5.2mmol), and(E)-4-(1-(4-fluorophenyl)ethylideneamino)isobenzofuran-1(3H)-one (1 g,3.7 mmol) in ethyl propionate (20 ml) was added rapidly EtONa [sodium(340 mg, 14.8 mmol) in 8 mL ethanol] at 0° C., then the mixture wasstirred at 30° C. for 3 hr. The resulting mixture was added ethylacetate (150 mL) and washed with water (25 mL×3), the organic layerswere combined and evaporated to dryness to give the crude product, whichwas purified by column chromatography (silica gel,dichloromethane:methanol=200:1 to 50:1) to afford the title compound asa red solid (120 mg, yield 8%). LC-MS (ESI) m/z: 408 (M+1)⁺

Example 151C8-(4-Fluorophenyl)-8-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl2-(4-fluorophenyl)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(120 mg, 0.30 mmol) in methanol (4 mL) was added hydrazine monohydrate(0.7 mL) at room temperature, the mixture was stirred under 30° C. for10 hr. The solvent was evaporated to obtain crude solid, which waswashed by 14 mL of mixture of ethyl acetate and methanol (13:1) toobtain the title compound as a green solid (40 mg, yield 36%). LC-MS(ESI) m/z: 376 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□ δ (ppm): 1.39 (s,3H), 3.71 (s, 3H), 4.74 (s, 1H), 6.72 (s, 1H), 7.03 (s, 1H), 7.06-7.11(m, 2H), 7.16-7.19 (d, J=8 Hz, 1H), 7.25-7.28 (d, J=8 Hz, 1H), 7.49 (s,1H), 7.54-7.58 (m, 3H), 12.05 (s, 1H).

Example 152 Racemate of(8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;and racemate of(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 152A Ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

To a solution of(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one(4.2 g, 13.5 mmol) and compound1-methyl-1H-1,2,4-triazole-5-carbaldehyde (3.0 g, 27 mmol) in ethylpropionate (150 mL) was added rapidly NaOEt [sodium (870 mg, 37.8 mmol)in 70 mL ethanol] at 40° C., then the mixture was stirred at 48° C. for3 hr. The resulting mixture was concentrated under reduced pressure andextracted with ethyl acetate (250 mL×3). The extract was evaporated togive a crude product, which was purified by column chromatography(silica gel, dichloromethane:methanol=50:1 to 10:1) to obtain the titlecompound (560 mg, yield 9%) (a mixture of cis and trans isomers). LC-MS(ESI) m/z: 452 (M+1)⁺.

Example 152B Racemate of(8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;and racemate of(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

To a solution of ethyl2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate(560 mg, 1.24 mmol, a mixture of cis and trans isomers) in methanol (2mL) was added hydrazine monohydrate (0.5 mL) and the mixture was stirredunder 25° C. for 10 hr. The mixture was concentrated in vacuum and theresidue was purified by prep-TLC then prep-HPLC to obtain the two pairsof diastereomers as white solids (racemate of(8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:20 mg, yield 4%). LC-MS (ESI) m/z: 420 (M+1)⁺; ¹H-NMR (400 MHz, DMSO-d₆)□□ δ (ppm): 2.16 (s, 6H), 2.88 (s, 3H), 3.34 (s, 2H), 4.73-4.74 (d,J₂=4.0 Hz, 1H), 5.02-5.03 (d, J₂=4.0 Hz, 1H), 6.92-6.95 (dd, J₁=10.8 Hz,J₂=2.4 Hz, 1H), 7.07-7.09 (dd, J₁=10.8 Hz, J₂=2.4 Hz, 1H), 7.04-7.06 (d,J=7.6 Hz, 2H), 7.23-7.25 (d, J=7.6 Hz, 2H), 7.56 (s, 1H), 7.69 (s, 1H),12.45 (s, 1H). Racemate of(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one:140 mg, yield 27%). LC-MS (ESI) m/z: 420 (M+1)⁺; ¹H-NMR (400 MHz,DMSO-d₆) □□ δ (ppm): 2.10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H), 4.91-4.99(m, 2H), 6.91-6.95 (dd, J₂=11.2 Hz, 1H), 7.05-7.08 (dd, J₂=9.2 Hz, 1H),7.20-7.23 (d, J=8.0 Hz, 2H), 7.35-7.37 (d, J=8.0 Hz, 2H), 7.72 (s, 1H),7.79 (s, 1H), 12.33 (s, 1H).

Example 153 Racemate of(8S,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8R,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

A racemate of(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one(600 mg, 1.67 mmol) was added to 30% NaOH (32 mL) at room temperature,the mixture was stirred at 85° C. for 3 hr. Then the solution was cooledto 5° C. and filtered to obtain 555 mg of white solid, which waspurified by prep-HPLC to obtain the title compound as white solid (40mg, yield 7%). LC-MS (ESI) m/z: 362 (M+1)⁺. ¹H-NMR (400 MHz, DMSO-d₆) □□δ (ppm): 2.74 (s, 3H), 4.47 (d, J=4 Hz, 1H), 4.90 (d, J=4 Hz, 1H), 6.65(s, 1H), 6.81 (s, 1H), 7.07-7.17 (m, 6H), 7.40-7.42 (d, J=8 Hz, 1H),7.55-7.59 (t, J=8 Hz, 1H), 12.23 (s, 1H).

Examples on Chiral Resolution Example 154 Enantiomers of(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

8-(4-Fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in DMF and chiral resolution was performed usingsuper-fluid chromatography (SFC) with IA chiral column and methanol(30%) and CO₂ (70%) as the eluents.

Example 155 Enantiomers of(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in DMF and chiral resolution was performed usingsuper-fluid chromatography (SFC) with IA chiral column and methanol(20%) and CO₂ (80%) as the eluents.

Example 156(8R,9S)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in DMF and chiral resolution was performed usingsuper-fluid chromatography (SFC) with IA chiral column and methanol(30%) and CO₂ (70%) as the eluents.

Example 157(8R,9S)-8-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

8-(4-Fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in DMF and chiral resolution was performed usingsuper-fluid chromatography (SFC) with IA chiral column and methanol(30%) and CO₂ (70%) as the eluents.

Example 158(8R,9S)-8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in methanol and chiral resolution was performed usingsuper-fluid chromatography (SFC) with OJ-H chiral column and methanol(40%) and CO₂ (60%) as the eluents

Example 159(8R,9S)-8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneand(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-onewas dissolved in methanol and chiral resolution was performed usingsuper-fluid chromatography (SFC) with AS-H chiral column and methanol(20%) and CO₂ (80%) as the eluents.

Biological Studies

Inhibitory effects of test compounds against human PARP 1 enzyme wasassessed using Trevigen's Universal Chemiluminescent PARP Assay Kit(Trevigen CAT #4676-096-K) following the manufacturer's recommendedprotocol.

Immediately prior to performing the assay, the following reagents wereprepared: A) 20×PARP Assay Buffer was diluted to 1× with dH₂O; B)10×PARP Cocktail, which contains a mixture of NAD and biotinylated NAD,was diluted by the addition of 10× Activated DNA and 1×PARP AssayBuffer. Both the PARP Cocktail and Activated DNA are 1× after thedilution; C) all test compounds were initially dissolved in DMSO, andsubsequently serial diluted with 1×PARP Assay Buffer; D) recombinanthuman PARP 1 enzyme was diluted with 1×PARP Assay Buffer to generate 0.5unit/15 μl; E) 10× Strep-Diluent was diluted to 1× with 1×PBS/0.1%Triton X-100; F) Just before use, dilute Strep-HRP 500-fold with 1×Strep-Diluent.

The chemiluminescent assays for PARP activity were performed in white96-well plates that are pre-coated with histones. Briefly, strip wellswere removed from the wrapper, 50 μl/well of 1×PARP Buffer was added torehydrate the histones and incubation was allowed for 30 minutes at roomtemperature. Removal of the 1×PARP Buffer from the wells wasaccomplished by tapping the strip wells on paper towel. Serial dilutionsof the test compounds were added to duplicate wells in 10 μl/wellvolume. Final assay concentrations of test compounds were typicallybetween 1 and 0.0001 μM. Subsequently, recombinant human PARP 1 enzymewas added to 0.5 unit of PARP 1 enzyme/well in 15 μl/well volume.Combined volume of enzyme and inhibitor was 25 μl. Incubate theenzyme/inhibitor mixtures for 10 minutes at room temperature. To startthe reaction, 25 μl/well of the 1×PARP Cocktail was added to all thewells. Controls included background wells with 1× Assay Buffer alone (noPARP) and wells with no inhibitor for determining the maximum or 100%PARP activity value. In all cases the final reaction volume was 50 μl.

The reactions were allowed to proceed for 1 hour at room temperature.The plate was then washed 4 times with 200 μl/well 1×PBS/0.1% TritonX-100, using EL×50 Automated Strip Washer (BIO-TEK). After washing, allwells were incubated for 60 minutes with 50 μl/well Strep-HRP, diluted1:500 with 1× Strep-Diluent. The plate was washed 4 times with 200μl/well 1×PBS/0.1% Triton X-100 using EL×50 Automated Strip Washer(BIO-TEK). After washing, dry the wells by tapping plate onto papertowels. Mix equal volumes of PeroxyGlow™ A and B together and add 100 μlper well. The light output was immediately determined in a plate reader(EnVision, by Perkin Elmer) set up for measuring chemiluminescence.

The % enzyme activity for each compound is then calculated using thefollowing equation:

${\% \mspace{14mu} {Inhibition}} = {\frac{{{Activity}\mspace{14mu} {Ctrl}} - X}{{{Activity}\mspace{14mu} {Ctrl}} - {{Negative}\mspace{14mu} {Ctrl}}} \times 100\%}$

IC₅₀ values (the concentration at which 50% of the enzyme activity isinhibited) of each test compound were calculated using GraphPad Prism5software.

All of the compounds tested had or were expected to have enzymatic PARPinhibitory activity. Of the compounds tested, over 100 compounds had aPARP inhibitory activity in the enzymatic assay of less than 50 nM, withapproximately 60 of these compounds having an inhibitory activity ofless than 5 nM.

Chemosensitization assay determines the extent by which a PARP inhibitorenhances the tumor cell-killing effect of cytotoxic drugs expressed asPF₅₀ (potentiation factor at GI₅₀)]. 8000 LoVo cells were seeded intoeach well of a flat-bottomed 96-well microtiter plate in a volume of 50μl and incubated in F12K containing 10% (v/v) FBS (medium) overnight at37° C. Cells were added with 50 μl medium alone, medium containing 2 μMPARP inhibitor, medium containing increasing concentration ofTemozolomide (0-2000 μM), and medium containing 2 μM PARP inhibitor andincreasing concentration of Temozolomide (0-2000 μM). Finalconcentration range for Temozolomide was 0-1000 μM where applicable,final concentration of PARP inhibitor was 1 μM where applicable. Finalconcentration of DMSO was 1% in each well. Cells were allowed to growfor 5 days before cell survival was determined by CellTiter Glo staining(Promega, Madison, Wis., USA). Cell growth, determined after subtractionof time 0 values, was expressed as a percentage of the control well thatcontained medium with 1% DMSO. GI₅₀ (concentration of drug thatinhibited growth by 50%) values were calculated from the computergenerated curves (GraphPad Software, Inc. San Diego Calif.). Thepotentiation factor [PF₅₀ (potentiation factor at GI₅₀)] was calculatedas GI₅₀ of Temozolomide alone/GI₅₀ of Temozolomide+PARP inhibitor.Reference: Thomas H. D. et al. (2007). Preclinical selection of a novelpoly(ADP-ribose) polymerase inhibitor for clinical trial. MolecularCancer Therapy 6, 945-956.

Most of the compounds tested had a PF50 of more than 2×.

Xenograft Studies Antitumor In Vivo Animal Efficacy Study

Female athymic nu/nu mice (8-10 weeks old) were used for all in vivoxenograft studies. Mice were quarantined for at least 1 week beforeexperimental manipulation. Exponentially growing cells or in vivopassaged tumor fragments were implanted subcutaneously at the rightflank of nude mice. Tumor-bearing mice were randomized according totumor size into 6-8 mice/group in each study (average tumor size ˜150mm³). Mice were observed daily for survival and tumors were measuredtwice weekly by caliper in two dimensions and converted to tumor massusing the formula for a prolate ellipsoid (V=0.5 a×b²), where a and bare the long and short diameters of the tumor, respectively, andassuming unit density (1 mm³=1 mg).

Single agent activity: PARP inhibitors were evaluated in Capan-1 andMX-1 xenografts for single agent activities. Compounds were dosed orally(p.o.), once daily for 28 days in vehicle 10% DMAc/6% Solutal/84% PBS,and the same vehicle was used as control. Mice were continuouslymonitored for 10 more days after the last day of dosing.

Combination study: PARP inhibitory compounds described herein in vehicle10% DMAc/6% Solutal/84% PBS, were either administered orally, once dailyfor 5 days with Temozolomide (17 mg/kg or 34 mg/kg, p.o., qdx5, 30 minafter each dose of compounds) in SW620 xenograft model or dosed orally,once daily for 8 days with 6 mg/kg Cisplatin (once by ip on day 3, 30min after first dose of PARP inhibitors) in MX-1 xenograft model. Micewere observed and individual tumor was measured for 30 more days afterthe last dosing of PARP inhibitory compounds.

In vivo animal study on a few potent PARP inhibitory compounds describedin the Examples section have demonstrated single agent activities inreducing both MX-1 and Capan-1 tumor growth by themselves whenadministered orally for 28 days. A few compounds when combined with DNAdamaging agent Temozolomide significantly slowed tumor progression inSW620 model. In the MX-1 breast xenograft model, these compoundspotentiated the platinum drug Cisplatin causing regression ofestablished tumors, whereas with comparable doses of cisplatin or PARPinhibitor alone, only small to modest tumor inhibition was exhibited.

BRCA2-Deficient V-C₈ or BRCA2-Complimented V-C₈+B2 Cells

BRCA2-deficient V-C₈ or BRCA2-complimented V-C₈+B2 cells are implantedintramuscularly into the thigh of 40 CD-1 nude mice. Treatments areinitiated when tumors are of measurable size (approximate leg diameterof 11 mm). Animals receive either a compound of Formula (I), (IA) or(II) (two doses of 25 or 50 mg/kg in saline) or saline (10 mg/ml)intraperitoneallly administered on days 1-5, and are monitored on adaily basis during treatment (tumor measurements, body weights andclinical evidence are recorded); and as required after the lasttreatment.

ES-Cell-Derived Tumors

ES-cell-derived tumors (teratomas) are produced by subcutaneousinjection of 2×10⁶ ES cells into 6-8 week athymic BALB/c-nude (nu/nu)mice. 40 mice are injected with BRCA2-deficient ES cells or isogenicwild-type cells. Two days after cell injection, treatment with acompound of Formula (I), (IA) or (II) is initiated. For threeconsecutive days, two intraperitoneal doses of a compound of Formula(I), (IA) or (II) or vehicle is administered, 6 h apart, each at adosage of 15 mg/kg per animal. This treatment is stopped for 5 days andthen re-initiated for another three consecutive days. Growth of tumorsis monitored from a minimum volume of 0.2 cm³.

The in vitro assays disclosed herein, along with other known in vitroassays (Farmer et al., Nature 2005; 434:913-7: clonogenic survival assayfinding that a BRCA2-deficient cell line V-C₈, compared with the BRCA2wild type control exhibited sensitivity to AG14361, a PARP-1 inhibitor,(Ki=5 nm) and NU1025, a moderately potent PARP-1 inhibitor (Ki=50 nM); &Mcabe et al., Cancer Biology & Therapy 2005; 4:9, 934-36; clonogenicsurvival assay using CAPAN-1 cells maintained in DMEM supplemented withFCS (20% v/v), glutamine and antibiotics showing sensitivity to PARPinhibition using KU0058684) demonstrates the activity of PARP-inhibitorsin a static test situation. Additionally, animal models have been usedto analyze the relationship between in vitro tests and parameters of invivo efficacy. By way of example only, Farmer et al., has shown in vivoefficacy in blocking the growth of BRCA2-deficient tumors usingKU0058684, a PARP-1 inhibitor. Nature 2005; 434:913-7. This indicatesthat PARP-1 inhibition is a viable cancer treatment for BRCA1/2 mutationcarriers. Furthermore, KU0059436, a PARP-1 inhibitor is currently inPhase I clinical trials for patients with advanced solid tumors. Giventhis information, compounds of Formula (I), (IA) or (II) which haveshown in vitro inhibitory action are likely to show analogous in vivo(mouse and human) efficacy.

Phase II Clinical Trial of the Safety and Efficacy of Compounds ofFormula (I), (IA) or (II)

The purpose of this phase II trial is to study the side effects and bestdose of a compound of Formula (I), (IA) or (II) and to determine howwell it works in treating patients with locally advanced or metastaticbreast cancer or advanced ovarian cancer.

Objectives:

-   -   Primary:        -   A. To determine the response rate to a compound of Formula            (I), (IA) or (II) in patients with locally advanced or            metastatic breast or advanced ovarian cancer shown to            express the BRCA 1 or 2 mutations        -   B. To evaluate the toxicity of a compound of Formula (I),            (IA) or (II) in these patients    -   Secondary:        -   A. To evaluate the time to progression and overall survival            in patients treated with a compound of Formula (I), (IA) or            (II)        -   B. To study pharmacokinetics of a compound of Formula (I),            (IA) or (II) in these patients        -   C. To evaluate the Poly(ADP-ribose) polymerase (PARP)            activity in peripheral blood lymphocytes from BRCA 1 and 2            heterozygotic patients    -   Tertiary:        -   A. To evaluate PARP expression using quantitative western            blotting immuno-assays        -   B. To investigate pharmacogenomics, including CYP2D6 and            CYP3A5, drug transport proteins, as well as polymorphisms in            the genes coding for the PARP enzymes themselves        -   C. To analyze tumor biopsy samples (when possible) for BRCA            mutation status, PARP activity, and PARP expression        -   D. To analyze paraffin sections from original diagnostic            biopsies/operative procedures (when available) for DNA            repair enzyme status using immunohistochemical techniques        -   E. To analyze cells obtained from ascitic or pleural fluid            (where available) for primary cell culture for DNA double            strand break repair pathway function            Patients: Eligible subjects will be men and women 18 years            and older

Criteria:

-   -   Disease Characteristics:        -   Histologically confirmed locally advanced or metastatic            breast cancer or advanced ovarian cancer        -   Must meet 1 of the following criteria:            -   Proven a carrier of a known mutation of BRCA 1 or BRCA 2            -   Considered highly likely a carrier of BRCA 1 or 2                mutation (score of ≥20 per Manchester criteria)        -   No more than 3 prior chemotherapy regimens for patients with            breast or ovarian cancer            -   More than 2 months since prior carboplatin- or                cisplatin-containing chemotherapy for ovarian cancer        -   Measurable disease, as defined by RECIST criteria and            measured by x-ray, CT scan, or MRI            -   Patients with bone disease must have other measurable                disease for evaluation            -   Previously irradiated lesions cannot be used for                measurable disease        -   No known brain metastases        -   Hormone receptor status not specified    -   Patient Characteristics:        -   WHO performance status 0-1        -   Life expectancy ≥12 weeks        -   Menopausal status not specified        -   Hemoglobin ≥9.0 g/dL        -   Absolute neutrophils ≥1,500/mm³        -   Platelets ≥100,000/mm³        -   Serum bilirubin ≤1.5 times upper limit of normal (ULN)        -   ALT or AST ≤2.5 times ULN (≤5 times ULN if due to tumor)        -   Glomerular filtration rate (GFR) ≥50 mL/min        -   Not pregnant or nursing        -   Negative pregnancy test        -   Fertile patients must use two highly effective forms of            contraception (i.e., oral, injected, or implanted hormonal            contraception, intrauterine device, barrier method of condom            plus spermicide, or are surgically sterile) 4 weeks prior to            (females), during, and for 6 months after (males and            females) completion of study therapy        -   Able to cooperate with treatment and follow-up        -   No non-malignant systemic disease, including active            uncontrolled infection        -   No other concurrent malignancy, except adequately treated            cone-biopsied carcinoma in situ of the uterine cervix, basal            cell or squamous cell carcinoma of the skin, or breast and            ovarian carcinoma            -   Cancer survivors who have undergone potentially curative                therapy for a prior malignancy, have no evidence of that                disease for 5 years, and are deemed at low risk for                recurrence are eligible        -   No active or unstable cardiac disease or history of            myocardial infarction within the past 6 months            -   Patients with cardiovascular signs or symptoms should                have a MUGA scan or echocardiogram, and those with a                left ventricular ejection fraction (LVEF) below the                institutional limit of normal should be excluded        -   No other condition which, in the investigator's opinion,            would not make the patient a good candidate for this study

Prior Concurrent Therapy:

-   -   At least 4 weeks since prior radiotherapy (except for palliative        reasons), endocrine therapy, immunotherapy or chemotherapy (6        weeks for nitrosoureas and mitomycin C)    -   At least 4 weeks since prior major thoracic and/or abdominal        surgery and recovered    -   Concurrent radiotherapy for the control of bone pain or skin        lesions allowed, but not within 5 days of the last dose of study        drug    -   Concurrent bisphosphonates allowed provided the dose is stable        and treatment was started at least 2 weeks prior to recruitment    -   No unresolved toxicities (CTCAE ≥grade 1) from prior treatments        (except for alopecia)    -   No concurrent anticancer therapy or investigational drugs    -   No concurrent tetracycline antibiotic therapy for prolonged        periods (short courses [5-7 days] for treatment of infection are        allowed)

Study Design: This is a dose-escalation study followed by an open labelmulticenter study. Patients will be stratified according to tumor type(breast vs ovarian) and mutation status (BRCA 1 vs BRCA 2). Patientswill receive a compound of Formula (I), (IA) or (II) (at one of severalpossible dosages) over 30 minutes once daily on days 1-5. Treatmentrepeats every 21 days for 12 courses in the absence of diseaseprogression or unacceptable toxicity. Patients who achieve stable orresponding disease may receive additional courses of treatment at thediscretion of the chief investigator or Drug Development Office (DDO).Patients will undergo blood sample collection periodically forpharmacokinetic and pharmacodynamic studies. Samples will be analyzedfor tumor marker (CA 125 or CA 15.3) measurements, plasma levels of acompound of Formula (I), (IA) or (II) via liquid chromatography/massspectrometry/mass spectrometry, PARP activity, and PARP proteinexpression via western blotting immunoassays. Paraffin embedded sectionsfrom original diagnostic biopsy are also collected and analyzed for PARPprotein expression via immunohistochemical technique. Pleural andascitic fluid may be collected and analyzed for DNA DS break repairproficiency via immunohistochemical technique. Some patients will alsoundergo biopsy of tumors and samples will be analyzed for BRCA 2mutation as well as PARP activity via validated PARP immunoblottingassay. After completion of the study treatment, patients will befollowed for 28 days.

Primary Outcome Measures:

-   -   Assessment of antitumor activity according to RECIST using tumor        size measured clinically or radiologically with CT scan, MRI,        plain x-ray, or other imaging techniques    -   Safety profile

Secondary Outcome Measures:

-   -   Time to progression and overall survival    -   Plasma levels by Liquid Chromatography/Mass Spectrometry/Mass        Spectrometry    -   Poly(ADP-ribose) polymerase (PARP) activity measured ex vivo        using validated assays    -   PARP expression using quantitative Western blotting        immuno-assays    -   Pharmacogenomics including CYP2D6 and CYP3A5, drug transport        proteins, as well as polymorphisms in the genes coding for the        PARP enzymes themselves    -   BRCA mutation status, PARP activity, and PARP expression in        tumor biopsy samples (when possible)    -   DNA repair enzyme status using immunohistochemical techniques in        paraffin sections from original diagnostic biopsies/operative        procedures (where available)    -   DNA double strand break repair pathway function in cells        obtained from ascitic or pleural fluid (where available) for        primary cell culture

1-26. (canceled)
 27. A method of treating lung cancer in a subject,comprising administering to the subject a therapeutically effectiveamount of5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,or a pharmaceutically acceptable salt or solvate thereof.
 28. The methodof claim 27, wherein said administration is in combination with ionizingradiation, one or more chemotherapeutic agents, or a combinationthereof.
 29. The method of claim 28, wherein the compound is used incombination with one or more chemotherapeutic agents, wherein eachchemotherapeutic agent is independently methyl methanesulfonate,temozolomide, dacarbazine (DTIC), a topoisomerase-1 inhibitor,Topotecan, Irinotecan, Rubitecan, Exatecan, Lurtotecan, Gimetecan,Diflomotecan, a homocamptothecin, Doxorubicin, a platinum basedantineoplastic agent, a 7-substituted non-silatecan, a 7-silylcamptothecin, paclitaxel, cetuximab, daunorubicin, methotrexate, ahormone, an antiestrogen, an antiandrogen, a gonadotropin releasinghormone analog, an interferon, alpha interferon, a tyrosine kinaseinhibitor, gefitinib, imatinib, gemtuzumab, or BNP
 1350. 30. The methodof claim 28, wherein the compound is used in combination with one ormore chemotherapeutic agents, wherein each chemotherapeutic agent isindependently irinotecan, cisplatin, carboplatin, paclitaxel, ortemozolomide.
 31. The method of claim 27, wherein the subject is ahuman.
 32. The method of claim 28, wherein the subject is a human. 33.The method of claim 29, wherein the subject is a human.
 34. The methodof claim 30, wherein the subject is a human.
 35. A method of treatinglung cancer in a subject, comprising administering to the subject atherapeutically effective amount of(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,or a pharmaceutically acceptable salt or solvate thereof.
 36. The methodof claim 35, wherein said administration is in combination with ionizingradiation, one or more chemotherapeutic agents, or a combinationthereof.
 37. The method of claim 36, wherein the compound is used incombination with one or more chemotherapeutic agents, wherein eachchemotherapeutic agent is independently methyl methanesulfonate,temozolomide, dacarbazine (DTIC), a topoisomerase-1 inhibitor,Topotecan, Irinotecan, Rubitecan, Exatecan, Lurtotecan, Gimetecan,Diflomotecan, a homocamptothecin, Doxorubicin, a platinum basedantineoplastic agent, a 7-substituted non-silatecan, a 7-silylcamptothecin, paclitaxel, cetuximab, daunorubicin, methotrexate, ahormone, an antiestrogen, an antiandrogen, a gonadotropin releasinghormone analog, an interferon, alpha interferon, a tyrosine kinaseinhibitor, gefitinib, imatinib, gemtuzumab, or BNP
 1350. 38. The methodof claim 36, wherein the compound is used in combination with one ormore chemotherapeutic agents, wherein each chemotherapeutic agent isindependently irinotecan, cisplatin, carboplatin, paclitaxel, ortemozolomide.
 39. The method of claim 35, wherein the subject is ahuman.
 40. The method of claim 36, wherein the subject is a human. 41.The method of claim 37, wherein the subject is a human.
 42. The methodof claim 38, wherein the subject is a human.